Benzofuran-2-sulfonamides pyridine derivatives as chemokine receptor modulators

ABSTRACT

The present invention relates to novel benzofuran-2-sulfonamide pyridine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors.

RELATED APPLICATION

This application claims the benefit of U.S. Non Provisional applicationSer. No. 13/782,174, filed Mar. 1, 2013, which claims the benefit ofU.S. Provisional Application Ser. No. 61/605,300, filed Mar. 1, 2012,which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel benzofuran-2-sulfonamide pyridinederivatives, processes for preparing them, pharmaceutical compositionscontaining them and their use as pharmaceuticals as modulators ofchemokine receptors. The invention relates specifically to the use ofthese compounds and their pharmaceutical compositions to treat disordersassociated with chemokine receptor modulation.

BACKGROUND OF THE INVENTION

Chemokines are a group of 7- to 14-kd peptides that play an importantrole in orchestrating leukocyte recruitment and migration duringinflammation, and therefore represent an important target foranti-inflammatory therapies (Wells et al., 2006). They act by binding toseven-transmembrane, G protein-coupled receptors, the chemokinereceptors. The chemokine system is complex, with about 50 chemokines and20 chemokine receptors identified in humans, often acting withredundancy, making selection of specific antagonists difficult (Gerardand Rollins, 2001). Genetic knockout strategies have confirmed theimportance of chemokines as regulators of immune function, but thedeletion of specific chemokines has led to only specific and relativelymild defects in the inflammatory response further emphasizing thecomplex redundancy of the system. Selectivity is crucial for use ofchemokine receptor antagonists in systemic diseases where a singlechemokine-receptor system is implicated such as atheroscelorsis wherethe macrophagemonocyte system is the major player in order to allow asubtle and specific control over immune function (Weisberg et al., 2006;Feria and Diaz Gonzalez et al., 2006).

Many ocular conditions are characterized by inappropriate migration andinfiltration of cells such as leukocytes and endothelial cells into theeye with deleterious effects to ocular structures (Wallace et al.,2004). Chemokines have been identified in such diseases andmisregulation of the chemokine system is apparent in corneal graftrejection, diabetic retinopathy, age-related macular degeneration(ARMD), chronic inflammatory diseases such as uveitis, dry eye etc. Micelacking CCR2 or MCP-1 develop features of ARMD with age, includingdrusen deposits, choroidal neovascularization and photoreceptor atrophyindicating a crucial role for this chemokine and its receptor signaling(Amabati et al., 2003). Thus CCR2 receptor-specific inhibitor might havepotential therapeutic benefit in ocular diseases like ARMD. In contrast,various human and animal studies have identified several chemokines indifferent forms of uveitis, produced both by resident and infiltratingcells, that strongly suggests a prominent role for these molecules inits pathogenesis. Studies in rat and mice models of uveitis havedemonstrated up-regulation of monocyte chemoattractant protein-1(MCP-1), macrophage inflammatory protein-1 (MIP-1), RANTES, stromalderived factor-1 (SDF-1) which are powerful chemoattractants formonocytes and T-cells (Fang et al., 2004; Keino et al., 2003). Similarfindings have been reported in peripheral blood mononuclear cells inpatients with acute anterior uveitis (AAU), the most common form ofhuman uveitis (Klitgaard et al., 2004). MCP-1 knockout mice and CCR5knockout mice show reduced endotoxin-induced uveitis, which is theanimal model for AAU (Takeuchi et al., 2005; Tuallion et al., 2002). Ithas also been demonstrated that blocking the chemokine system upstreamwith the use of NF-κB blockers significantly attenuates experimental AAUin rats (Yang et al., 2005). Blockage of NF-κB results intranscriptional inhibition of multiple chemokines. Given the complexityof pathogenesis in uveitis it is unlikely that a selective inhibition ofa chemokine receptor in monotherapy will offer therapeutic benefit. Asimilar role of multiple chemokines have been shown to be correlatedwith clinical stage of disease in diabetic retinopathy and dry eye(Meleth et al., 2005; Yamagami et al., 2005). In these ocular diseasesthe use of broad spectrum chemokine receptor inhibitor which inhibitsthe function of a wide range of chemokines may be beneficial.

The first broad spectrum chemokine inhibitor (BSCI) to be reported wastermed Peptide 3, which was derived from the sequence of human chemokineMCP-1 and was shown to block the migration of monocytes in response toMCP-1, MIP-1, RANTES and SDF-1 (Reckless and Grainger. 1999). A cyclicretro inverse analogue of Peptide 3, constructed of D-amino acids in thereverse sequence, called NR58-3.14.3 was observed to be a more potentchemokine inhibitor (Beech et al., 2001). NR58-3.14.3 has been used totest for anti-inflammatory activities in animal models ofatherosclerosis, lung inflammation, irritable bowel syndrome etc (Beechet al., 2001; Grainger and Reckless. 2003; Tokuyama et al., 2005).However there are several disadvantages to using these BSCI as along-term therapeutic strategy. The known BSCIs which are peptides whichhave relatively low potency, poor pharmacokinetics, and are unstable invivo. In addition, systemic use of broad spectrum chemokine receptorinhibitors could potentially lead to deleterious side effects due totheir systemic anti-inflammatory activity. However in ocular diseases, alocal or topical application would prevent the broad spectrum inhibitorto be taken up systemically. Identification of a small moleculeinhibitor of several chemokine receptors could be very useful fortreatment of inflammatory ocular diseases. Given the evidence for therole of multiple chemokines in several ocular diseases and theseresults, we propose that the use of small and large molecule broadspectrum chemokine receptor inhibitors will have utility in the localtreatment of ocular inflammatory diseases including, but not limited to,uveitis, dry eye, diabetic retinopathy, allergic eye disease andproliferative retinopathies. Manipulation of multiple chemokinestherefore represents a novel therapeutic approach in treating oculardiseases.

WO2008008374 discloses CCR2 inhibitors and methods of use thereof.

WO03099773 discloses CCR9 inhibitors and methods of use thereof.

US2012014997 discloses CCR9 inhibitors and methods of use thereof.

U.S. Pat. No. 7,622,583 discloses heteroaryl sulfonamides as antagonistsof the CCR2 receptor.

US20110118248 discloses heteroaryl sulfonamides as antagonists of theCCR2 receptor.

U.S. Pat. No. 7,884,110 discloses CCR2 inhibitors and methods of usethereof.

US 20080293720 discloses pyridinyl sulfonamide modulators of chemokinereceptors.

Ser. No. 7,393,873 discloses arylsulfonamide derivatives.

SUMMARY OF THE INVENTION

A group of novel benzofuran-2-sulfonamide pyridine derivatives which arepotent and selective chemokine receptor modulators, has been nowdiscovered. As such, the compounds described herein are useful intreating a wide variety of disorders associated with modulation ofchemokine receptors. The term “modulator” as used herein, includes butis not limited to: receptor agonist, antagonist, inverse agonist,inverse antagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which have chemokinereceptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example in thetreatment of humans with diseases and conditions that are alleviated bychemokine receptor modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the individual geometrical isomers, enantiomers,diastereoisomers, tautomers, zwitterions and pharmaceutically acceptablesalts thereof:

wherein:

-   -   R¹ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R² is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R³ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁴ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁵ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is O, C(O), S, S(O), S(O)₂, —C(═NOR¹⁶)—;    -   a is 0 or 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is S, S(O) or S(O)₂;    -   a is 0 or 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is O;    -   a is 0 or 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is C(O);    -   a is 0 or 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R² is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R³ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁴ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁵ is hydrogen, halogen or substituted or unsubstituted C₁₋₆        alkyl;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is —C(═NOR¹⁶)—;    -   a is 0 or 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₈₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein:

-   -   R¹ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R² is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R³ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁴ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁵ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁶ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁸ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆        alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵;    -   R⁹ is O, C(O), S, S(O), S(O)₂, —C(═NOR¹⁶)—;    -   a is 1;    -   R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl,        CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆        alkyne, substituted or unsubstituted C₂₋₆ alkene or COR¹⁵;    -   R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl;    -   R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or        can from an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,        substituted or unsubstituted heterocycle or substituted or        unsubstituted C₆₋₁₀ aryl or can from an optionally substituted        heterocycle with R¹³;    -   R¹⁵ is hydrogen, hydroxyl, substituted or unsubstituted        heterocycle, substituted or unsubstituted C₆₋₁₀ aryl or        substituted or unsubstituted C₁₋₆ alkyl;    -   R¹⁶ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; and    -   R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆ alkyl.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is O, C(O), S, S(O) or S(O)₂;    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₁₋₆ alkyl, NR¹³R¹⁴,        substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl;    -   R¹³ forms an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ forms an optionally substituted heterocycle with R¹³; and    -   R¹⁸ is hydrogen.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is O, C(O), S, S(O) or S(O)₂;    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₁₋₆ alkyl, NR¹³R¹⁴,        substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl;    -   R¹³ forms an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ forms an optionally substituted heterocycle with R¹³; and    -   R¹⁸ is hydrogen.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is C(O);    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₁₋₆ alkyl, NR¹³R¹⁴,        substituted or unsubstituted C₆₋₁₀ aryl, substituted or        unsubstituted heterocycle, substituted or unsubstituted C₃₋₈        cycloalkyl;    -   R¹³ forms an optionally substituted heterocycle with R¹⁴;    -   R¹⁴ forms an optionally substituted heterocycle with R¹³; and    -   R¹⁸ is hydrogen.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is S, S(O) or S(O)₂;    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₆₋₁₀ aryl or substituted or        unsubstituted heterocycle; and    -   R¹⁸ is hydrogen.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is O, C(O);    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₆₋₁₀ aryl or substituted or        unsubstituted heterocycle; and    -   R¹⁸ is hydrogen.

In another aspect the invention provides a compound having Formula Iwherein

-   -   R¹ is hydrogen;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen, halogen, substituted or unsubstituted C₁₋₆        alkyl;    -   R⁸ is hydrogen;    -   R⁹ is O, C(O);    -   a is 1;    -   R¹¹ is substituted or unsubstituted C₆₋₁₀ aryl or substituted or        unsubstituted heterocycle; and    -   R¹⁸ is hydrogen.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 6 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₆cycloalkyl. Hydrogen atoms on alkyl groups can be substituted by groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, carboxylic acids, ketones, ethers, esters, aldehydes, orsulfonamides.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by groups including, but not limited to:halogens, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles, aromaticheterocycles, —OC₁₋₆ alkyl, —NH₂, —NO₂, amides, ethers, esters,carboxylic acids, aldehydes, ketones, sulfonamides groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one or more double bonds. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be substituted bygroups including, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, ethers, esters, aldehydes, ketones, carboxylic acids,sulfonamides groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₆ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected from O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted by groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, ethers, esters, aldehydes, carboxylic acids, ketones,sulfonamides groups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be monocyclic or polycyclicAryl can be substituted by groups including, but not limited to:halogens, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles, aromaticheterocycles, —OC₁₋₆ alkyl, —NH₂, —NO₂, amides, ethers, esters,carboxylic acids, ketones, aldehydes, sulfonamides groups.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y)” or wherein R^(x) and R^(y) are the same orindependently H or C₁₋₆ alkyl.

The term “ketone” as used herein, represents a group of formula“—C(O)R^(x)” wherein R^(x) is C₁₋₆ alkyl.

The term “ester” as used herein, represents a group of formula“—C(O)OR^(x)” wherein R^(x) is C₁₋₆ alkyl.

The term “ether” as used herein, represents a group of formula “—OR^(x)”wherein R^(x) is C₁₋₆ alkyl.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) are the same orindependently H or C₁₋₆ alkyl.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “amino” as used herein, represents a group of formula “—NH₂”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” (sulfone) as used herein, represents a group offormula “—SO₂—”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—O—P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom

Compounds of the invention are:

-   N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   tert-butyl    {3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]phenyl}carbamate;-   N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoic    acid;-   methyl    2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate;-   N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-methylpyridin-3-yl)methoxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoate;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoic    acid;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoate;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoate;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoic    acid;-   N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoic    acid;-   N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;-   2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic    acid;-   3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic    acid;-   2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoic    acid;-   2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoic    acid;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfanyl)methyl]benzoic    acid;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoic    acid;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoate;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoic    acid;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoic    acid;-   methyl    2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoate;-   2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoic    acid.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic acid and the like (Handbook of PharmaceuticalSalts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag HelveticaChemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the chemokine receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of chemokine receptors.Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated bychemokine receptor modulation.

Therapeutic utilities of chemokine receptor modulators are skininflammatory diseases and conditions, including, but are not limited to:rosacea (dilation of the blood vessels just under the skin), sunburn,chronic sun damage, discreet erythemas, psoriasis, atopic dermatitis,menopause-associated hot flashes, hot flashes resulting fromorchiectomyatopic dermatitis, photoaging, seborrheic dermatitis, acne,allergic dermatitis, irritant dermatitis, telangiectasia (dilations ofpreviously existing small blood vessels) of the face, rhinophyma(hypertrophy of the nose with follicular dilation), red bulbous nose,acne-like skin eruptions (may ooze or crust), burning or stingingsensation of the face, irritated and bloodshot and watery eyes,cutaneous hyperactivity with dilation of blood vessels of the skin,Lyell's syndrome, Stevens-Johnson syndrome, erythema multiforme minor,erythema multiforme major and other inflammatory skin diseases, actinickeratoses, arsenic keratoses, inflammatory and non-inflammatory acne,ichthyoses and other keratinization and hyperproliferative disorders ofthe skin, eczema, wound healing.

Therapeutic utilities of chemokine receptor modulators are ocularinflammatory diseases including, but not limited to, uveitis, dry eye,keratitis, allergic eye disease and conditions affecting the posteriorpart of the eye, such as maculopathies and retinal degenerationincluding non-exudative age related macular degeneration, exudative agerelated macular degeneration, choroidal neovascularization, diabeticretinopathy, acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;uveitis, retinitis, and choroiditis such as acute multifocal placoidpigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy,infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediateuveitis (pars planitis), multifocal choroiditis, multiple evanescentwhite dot syndrome (mewds), ocular sarcoidosis, posterior scleritis,serpiginous choroiditis, subretinal fibrosis and uveitis syndrome,Vogt-Koyanagi- and Harada syndrome; vascular diseases exudative diseasessuch as retinal arterial occlusive disease, central retinal veinocclusion, disseminated intravascular coagulopathy, branch retinal veinocclusion, hypertensive fundus changes, ocular ischemic syndrome,retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, centralretinal artery occlusion, branch retinal artery occlusion, carotidartery disease (CAD), frosted branch angitis, sickle cell retinopathyand other hemoglobinopathies, angioid streaks, familial exudativevitreoretinopathy, and Eales disease; traumatic surgical conditions suchas sympathetic ophthalmia, uveitic retinal disease, retinal detachment,trauma, conditions caused by laser, conditions caused by photodynamictherapy, photocoagulation, hypoperfusion during surgery, radiationretinopathy, and bone marrow transplant retinopathy; proliferativedisorders such as proliferative vitreal retinopathy and epiretinalmembranes, and proliferative diabetic retinopathy; infectious disorderssuch as ocular histoplasmosis, ocular toxocariasis, presumed ocularhistoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinaldiseases associated with HIV infection, choroidal disease associate withHIV infection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epithelitis.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular inflammatory diseases including,but not limited to, uveitis, dry eye, Keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy, acutemacular neuroretinopathy, central serous chorioretinopathy, cystoidmacular edema, and diabetic macular edema; uveitis, retinitis, andchoroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vascular diseases exudative diseases such asretinal arterial occlusive disease, central retinal vein occlusion,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with associated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigment epithelitis.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds and their pharmaceutically-acceptable salts may beadministered through different routes, including but not limited totopical eye drops, direct injection, application at the back of the eyeor formulations that may further enhance the long duration of actionssuch as a slow releasing pellet, suspension, gel, or sustained deliverydevices such as any suitable drug delivery system (DDS) known in theart. While topical administration is preferred, this compound may alsobe used in an intraocular implant as described in U.S. Pat. No.7,931,909.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of chemokine receptors.Thus, in further embodiments of the invention, there are providedmethods for treating a disorder associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The described benzofuran-2-sulfonamide derivatives wereprepared by methods as shown in Scheme 1. Those skilled in the art willbe able to routinely modify and/or adapt Scheme 1 to synthesize anycompounds of the invention covered by Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 12.0 and someintermediates' and reagents' names used in the examples were generatedwith software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000from MDL ISIS Draw 2.5 SP1. In general, characterization of thecompounds is performed according to the following methods:

NMR spectra are recorded on Varian 600 or Varian 300, in the indicatedsolvent at ambient temperature; chemical shifts in [ppm], couplingconstants in [Hz].

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates were preparedaccording to published procedures. Solvents were purchased fromcommercial sources in appropriate quality and used as received. Airand/or moisture-sensitive reactions were run under an Ar- orN₂-atmosphere.

Usually the compounds of the invention were purified by chromatography:CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm);Preparative thin layer chromatography (PTLC): Analtech (silica gel 60F₂₅₄, 500 or 1000 μm).

-   The following abbreviations are used in the examples:-   CH₂Cl₂ dichloromethane-   AcOH acetic acid-   NaOH sodium hydroxide-   MeOH methanol-   CD₃OD deuterated methanol-   HCl hydrochloric acid-   DMF dimethylformamide-   EtOAc ethyl acetate-   CDCl₃ deuterated chloroform-   CHCl₃ chloroform-   DMSO-d₆ deuterated dimethyl sulfoxide-   THF tetrahydrofuran-   K₂CO₃ potassium carbonate-   Et₃N triethylamine-   Na₂SO₄ sodium sulfate-   iPr₂NEt N,N′-diisopropylethylamine-   MPLC medium pressure liquid chromatography-   NH₄Cl Ammonium chloride-   mCPBA 3-Chloroperoxybenzoic acid-   KOH potassium hydroxide-   Et₂O diethylether-   EDCl 1-ethyl-3-(3-dimethylaminoprobyl)carbodiimide)-   POCl₃ Phosphoryl chloride-   TFA 2,2,2-Trifluoroethanoic add-   K₂CO₃ potassium carbonate-   Na₂S.9H₂O Sodium Sulfide Nonahydride

EXAMPLE 1 Intermediate 1 5-chloro-3-nitropyridine-2-thiol

To a solution of 2,5-dichloro-3-nitropyridine (524 mg, 2.70 mmol) indioxane (5 ml) and water (1 ml) was added Na₂S.9H₂O and the reaction wasstirred at rt for 2 hours. The reaction was quenched with 1N HCl andthen extracted with EtOAc (2×30 ml). The organic layer was washed withwater, brine and dried over Na₂SO₄ anhydride and concentrated in vacuo.The crude residue was purified by silica gel column chromatography (30%EtOAc in Hexane) to give Intermediate 1 (378 mg, 74%).

¹H NMR (600 MHz, CDCl₃) δ 8.54 (d, J=2.05 Hz, 1H), 8.51 (d, J=2.05 Hz,1H).

EXAMPLE 2 Intermediate 2 2-(benzylthio)-5-chloro-3-nitropyridine

A mixture of Intermediate 1 (332 mg, 1.74 mmol), (bromomethyl)benzene(299 mg, 1.74 mmol) and K₂CO₃ (1.2 g, 8.74 mmol) in DMF (10 ml) wasstirred at room temperature over night. The reaction mixture was pouredinto water (50 ml) and extracted with ethyl acetate (2×50 ml). Theorganic layer was washed with brine and then dried over Na₂SO₄anhydride, concentrated in vacuo and purified by column chromatography(0˜30% ethyl acetate in hexane) to give Intermediate 2 (417 mg, 85%).

¹H NMR (600 MHz, acetone) δ 8.88 (d, J=2.35 Hz, 1H), 8.65 (d, J=2.05 Hz,1H), 7.41-7.52 (m, 2H), 7.29-7.34 (m, 2H), 7.23-7.28 (m, 1H), 4.50 (s,2H).

EXAMPLE 3 Intermediate 3 2-(benzylthio)-5-chloropyridin-3-amine

Intermediate 2 (417 mg, 1.49 mmol) was dissolved in MeOH (30 ml). Zn(2.4 g, 37.23 mmol) and NH₄Cl (1 ml) was added to the solution. Afterthe mixture was stirred for 10 min at room temperature, the solid wasfiltered and the filtrate was concentrated in vacuo and then the cruderesidue was purified by column chromatography (0˜30% EtOAc in hexane) toafford Intermediate 3 (326 mg, 88%).

¹H NMR (600 MHz, acetone) δ 7.82 (d, J=2.05 Hz, 1H), 7.40 (d, J=7.63 Hz,2H), 7.28 (t, J=7.48 Hz, 2H), 7.18-7.24 (m, 1H), 7.03 (s, 1H), 4.44 (s,2H).

EXAMPLE 4 Compound 1N-[2-(benzylthio)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide

A mixture of Intermediate 3 (326 mg, 1.30 mmol) andbenzofuran-2-sulfonyl chloride (281 mg, 1.30 mmol) in pyridine (3 ml)was heated at 100° C. overnight. Pyridine was removed by reducedpressure and the residue was loaded on silica gel column directly andisolated Compound 1 with 30% EtOAc in Hexane (277 mg, 50%).

¹H NMR (600 MHz, acetone) δ 9.25 (br. s., 1H), 8.40 (d, J=2.35 Hz, 1H),7.71-7.79 (m, 2H), 7.50-7.61 (m, 2H), 7.44 (d, J=0.88 Hz, 1H), 7.38-7.42(m, 1H), 7.12-7.19 (m, 3H), 6.98-7.07 (m, 2H), 4.18 (s, 2H).

EXAMPLE 5 Compound 2N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 1 (219 mg, 0.509 mmol) in CH₂Cl₂ (10 ml) at 0°C. was added mCPBA (102 mg, 0.509 mmol). After it was stirred for 30 minat 0° C., the mixture was separated into two portions. One portion (5ml) was concentrated in vacuo and purified by silica gel columnchromatography (0˜100% EtOAc in hexane followed by 0˜10% MeOH in CH₂Cl₂)to give Compound 2 as a solid (92 mg).

¹H NMR (300 MHz, CD₃OD) δ 7.88 (s, 1H), 7.81 (br. s., 1H), 7.62-7.71 (m,1H), 7.03-7.45 (m, 9H), 4.52 (d, J=12.89 Hz, 1H), 4.25 (d, J=12.89 Hz,1H).

EXAMPLE 6 Compound 3N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide

To the other portion (5 ml) of the reaction from EXAMPLE 5 was addedmCPBA (110 mg, 0.548 mmol) and the reaction was stirred at rt for 2hours. The mixture was concentrated in vacuo and the residue waspurified by column chromatography on silica gel (0˜100% EtOAc in hexane)to give Compound 3 as a solid (63 mg).

¹H NMR (600 MHz, CD₃OD) δ 8.18 (d, J=2.05 Hz, 1H), 7.63-7.72 (m, 2H),7.32-7.45 (m, 3H), 7.23-7.30 (m, 1H), 7.08-7.15 (m, 3H), 6.95-7.04 (m,2H), 4.83 (s, 2H).

EXAMPLE 7 Intermediate 45-chloro-3-nitro-2-((pyridin-3-ylmethyl)thio)pyridine

To a solution of Intermediate 1 (416 mg, 2.19 mmol) in DMF (10 ml) wasadded 3-(bromomethyl)pyridine hydrobromide (554 mg, 2.19 mmol) and K₂CO₃(1.5 g, 10.95 mmol) and stirred at room temperature for 1 hour. Thereaction mixture was poured into water (50 ml) and extracted with ethylacetate (2×50 ml). The organic layer was washed with brine and thendried over Na₂SO₄, concentrated in vacuo and purified by flash columnchromatography on silica gel (0˜30% ethyl acetate in hexane) to giveIntermediate 4 (462 mg, 75%).

¹H NMR (600 MHz, CD₃OD) δ 8.80 (d, J=2.35 Hz, 1H), 8.65 (d, J=2.35 Hz,1H), 8.64 (d, J=2.05 Hz, 1H), 8.39 (dd, J=1.32, 4.84 Hz, 1H), 7.94 (ddd,J=1.61, 1.91, 8.22 Hz, 1H), 7.37 (dd, J=5.14, 7.48 Hz, 1H), 4.52 (s,2H).

EXAMPLE 8 Intermediate 55-chloro-2-((pyridin-3-ylmethyl)thio)pyridin-3-amine

To a solution Intermediate 4 (460 mg, 1.64 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (2.7 g, 41.07 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 5 (314 mg, 76%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CD₃OD) δ 8.47 (d, J=1.76 Hz, 1H), 8.35 (dd, J=1.47,4.99 Hz, 1H), 7.81 (dt, J=1.91, 7.92 Hz, 1H), 7.77 (d, J=2.05 Hz, 1H),7.23-7.41 (m, 1H), 6.98 (d, J=2.35 Hz, 1H), 4.38 (s, 2H).

EXAMPLE 9 Compound 4N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To Intermediate 5 (310 mg, 1.24 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (268 mg, 1.24 mmol) and the reaction wasstirred at 100° C. for 16 hours, then additional benzofuran-2-sulfonylchloride (268 mg, 1.24 mmol) was added and the mixture was heated foranother 24 hours and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (0-30% EtOAc inhexanes) to yield Compound 4 (201 mg, 38%).

¹H NMR (600 MHz, CD₃OD) δ 8.47 (s, 1H), 8.29 (d, J=4.70 Hz, 1H), 7.87(d, J=1.47 Hz, 1H), 7.66 (d, J=7.63 Hz, 1H), 7.59 (d, J=7.63 Hz, 1H),7.50 (d, J=2.35 Hz, 1H), 7.46 (d, J=8.22 Hz, 1H), 7.36 (td, J=1.03, 7.85Hz, 1H), 7.17-7.29 (m, 2H), 7.08 (s, 1H), 4.23 (s, 2H).

EXAMPLE 10 Compound 5N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To a solution of Compound 4 (77 mg, 0.18 mmol) in CH₂Cl₂ (10 ml) at 0°C. was added mCPBA (36 mg, 0.18 mmol). After it was stirred for 30 minat 0° C., the mixture was concentrated in vacuo and purified by silicagel column chromatography (0˜100% EtOAc in hexane followed by 0˜10% MeOHin CH₂Cl₂) to give Compound 5 (50 mg, 62%).

¹H NMR (600 MHz, CD₃OD) δ 8.32 (dd, J=1.17, 4.99 Hz, 1H), 8.05 (d,J=1.47 Hz, 1H), 7.87 (d, J=1.47 Hz, 1H), 7.76 (d, J=1.76 Hz, 1H), 7.68(d, J=7.63 Hz, 1H), 7.39-7.45 (m, 2H), 7.30-7.37 (m, 2H), 7.24-7.29 (m,J=7.63 Hz, 1H), 7.18 (dd, J=4.99, 7.63 Hz, 1H), 4.59 (d, J=13.21 Hz,2H), 4.45 (d, J=13.50 Hz, 1H).

EXAMPLE 11 Compound 6N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

and Compound 7N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1-benzofuran-2-sulfonamide

To a solution of Compound 4 (79 mg, 0.18 mmol) in CH₂Cl₂ (10 ml) wasadded mCPBA (92 mg, 0.46 mmol), and the solution was stirred at roomtemperature for 2 hours. It was concentrated in vacuo and purified bysilica gel column chromatography (0˜100% EtOAC in hexane followed by0˜10% MeOH in CH₂Cl₂) to isolate Compound 6 (11 mg) and Compound 7 (15mg).

Compound 6: ¹H NMR (600 MHz, CD₃OD) δ 8.44 (d, J=1.47 Hz, 1H), 8.35 (dd,J=1.17, 4.99 Hz, 1H), 8.14 (d, J=2.05 Hz, 1H), 7.72 (d, J=2.05 Hz, 1H),7.68 (d, J=7.92 Hz, 2H), 7.45 (d, J=8.22 Hz, 1H), 7.33-7.40 (m, 2H),7.23-7.32 (m, 1H), 7.17 (dd, J=4.99, 7.92 Hz, 1H), 5.15 (s, 2H).

Compound 7: ¹H NMR (600 MHz, CD₃OD) δ 8.40 (s, 1H), 8.19 (d, J=6.46 Hz,1H), 8.13 (d, J=2.05 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J=7.34 Hz, 1H),7.50 (d, J=8.51 Hz, 1H), 7.46 (d, J=7.92 Hz, 1H), 7.34-7.42 (m, 2H),7.26-7.33 (m, 2H), 5.15 (s, 2H).

EXAMPLE 12 Intermediate 6 2-(benzylthio)-3-nitropyridine

To a solution of 3-nitropyridine-2-thiol (1.0 g, 6.41 mmol) in DMF (30ml) was added (bromomethyl)benzene (1.10 g, 6.41 mmol) and K₂CO₃ (4.4 g,32.05 mmol), and the reaction was stirred at room temperature for 1hour. The reaction mixture was poured into water (50 ml) and extractedwith ethyl acetate (2×50 ml). The organic layer was washed with brineand then dried over Na₂SO₄, concentrated in vacuo and purified by flashcolumn chromatography on silica gel (0˜30% ethyl acetate in hexane) togive Intermediate 6 (1.49 g, 94%).

¹H NMR (600 MHz, CD₃OD) δ 8.70-8.79 (m, 1H), 8.55 (dd, J=1.17, 8.22 Hz,1H), 7.39-7.44 (m, 2H), 7.33 (dd, J=4.55, 8.36 Hz, 1H), 7.29 (t, J=7.63Hz, 2H), 7.19-7.25 (m, 1H), 4.48 (s, 3H).

EXAMPLE 13 Intermediate 7 2-(benzylthio)pyridin-3-amine

To a solution Intermediate 6 (1.49 g, 6.06 mmol) in MeOH (100 ml) wasadded saturated aqueous NH₄Cl (4 ml) and zinc dust (7.8 g, 121.1 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, and the filtrate was extracted with EtOAc (×2). The organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude Intermediate 7 (1 g, 76%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, CD₃OD) δ 7.80-7.84 (m, 1H), 7.25-7.30 (m, 2H),7.20-7.24 (m, 2H), 7.15-7.19 (m, 1H), 6.95-7.02 (m, 2H), 4.30 (s, 2H).

EXAMPLE 14 Compound 8N-[2-(benzylthio)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 7 (553 mg, 2.56 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (553 mg, 2.56 mmol), and the reaction wasstirred at 100° C. for 16 hours, then additional benzofuran-2-sulfonylchloride (553 mg, 2.56 mmol) was added, and the reaction was heated foranother 24 hours, and the mixture was concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 8 (800 mg, 79%).

¹H NMR (600 MHz, CD₃OD) δ 8.29 (dd, J=1.61, 4.84 Hz, 1H), 7.65 (d,J=7.92 Hz, 1H), 7.60 (dd, J=1.61, 7.78 Hz, 1H), 7.41-7.51 (m, 2H), 7.33(ddd, J=2.20, 5.94, 8.00 Hz, 1H), 7.24 (s, 1H), 7.01-7.14 (m, 4H), 6.92(dd, J=1.47, 7.63 Hz, 2H), 4.11 (s, 2H).

EXAMPLE 15 Compound 9N-[2-(benzylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 8 (228 mg, 0.58 mmol) in CH₂Cl₂ (10 ml) at 0°C. was added mCPBA (116 mg, 0.58 mmol). After it was stirred for 30 minat 0° C., the mixture was separated into two portions. One portion (5ml) was concentrated in vacuo and purified by silica gel columnchromatography (0˜100% EtOAC in hexane followed by 0˜10% MeOH in CH₂Cl₂)to give Compound 9 (205 mg, 86%).

¹H NMR (600 MHz, CD₃OD) δ 8.42 (dd, J=1.03, 4.55 Hz, 1H), 7.86 (dd,J=1.03, 8.36 Hz, 1H), 7.73 (d, J=9.10 Hz, 1H), 7.56 (d, J=8.51 Hz, 1H),7.47-7.52 (m, 2H), 7.44-7.47 (m, 1H), 7.32-7.38 (m, 1H), 7.11-7.22 (m,3H), 7.05 (d, J=7.04 Hz, 2H), 4.34 (d, J=12.91, 1H), 4.25 (d, J=13.21,1H).

EXAMPLE 16 Compound 10N-[2-(benzylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 8 (360 mg, 0.91 mmol) in CH₂Cl₂ (10 ml) atroom temperature was added mCPBA (365 mg, 1.82 mmol). After it wasstirred for 2 hours at room temperature, the mixture was concentrated invacuo and purified by silica gel column chromatography (0˜100% EtOAc inhexane) to give Compound 10 (124 mg, 32%).

¹H NMR (600 MHz, CD₃OD) δ 8.13 (dd, J=1.03, 8.95 Hz, 1H), 7.74 (dd,J=0.73, 4.26 Hz, 1H), 7.66 (d, J=7.34 Hz, 1H), 7.38-7.43 (m, 1H),7.32-7.37 (m, 2H), 7.23-7.31 (m, 2H), 7.08-7.17 (m, 3H), 6.95-7.05 (m,2H), 5.06 (s, 2H).

EXAMPLE 17 Intermediate 8 tert-butyl(3-(((3-nitropyridin-2-yl)thio)methyl)phenyl)carbamate

To 3-nitropyridine-2-thiol (532 mg, 3.41 mmol) in DMF (10 ml) was addedtert-butyl (3-(bromomethyl)phenyl)carbamate (976 mg, 3.41 mmol) andK₂CO₃ (2.35 g, 17.05 mmol) and the reaction was stirred at roomtemperature for 2 hours. The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (2×50 ml). The organic layer waswashed with brine and then dried over Na₂SO₄, concentrated in vacuo andpurified by flash column chromatography on silica gel (0˜30% ethylacetate in hexane) to give Intermediate 8 (1.22 g, 100%).

¹H NMR (600 MHz, CD₃OD) δ 8.76 (d, J=4.70 Hz, 1H), 8.55 (d, J=8.22 Hz,1H), 7.50 (s, 1H), 7.33 (ddd, J=1.17, 4.70, 8.22 Hz, 1H), 7.27 (d,J=7.92 Hz, 1H), 7.14-7.22 (m, 1H), 7.06 (d, J=7.63 Hz, 1H), 4.45 (s,2H), 1.51 (s, 9H).

EXAMPLE 18 Intermediate 9 tert-butyl(3-(((3-aminopyridin-2-yl)thio)methyl)phenyl)carbamate

To Intermediate 8 (1.18 g, 3.27 mmol) in MeOH (50 ml) and CH₂Cl₂ (5 ml)was added saturated aqueous NH₄Cl (3 ml) and zinc dust (5.3 g, 81.72mmol). The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 9 (908 mg, 84%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, acetone) δ 7.86 (d, J=4.40 Hz, 1H), 7.59-7.67 (m, 1H),7.41 (d, J=7.92 Hz, 1H), 7.17 (t, J=7.78 Hz, 1H), 7.03 (d, J=7.34 Hz,1H), 6.97 (d, J=7.63 Hz, 1H), 6.89 (dd, J=4.70, 7.92 Hz, 1H), 4.59 (br.s., 2H), 4.44 (s, 2H), 1.46 (s, 9H).

EXAMPLE 19 Intermediate 10{3-[3-(benzofuran-2-sulfonylamino)-pyridin-2-ylsulfanylmethyl]-phenyl}-carbamicacid tert-butyl Ester

and Compound 11N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To Intermediate 9 (908 mg, 2.74 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (592 mg, 2.74 mmol) and the reaction wasstirred at 100° C. for 16 hours, then additional benzofuran-2-sulfonylchloride (592 mg, 2.74 mmol) was added and the mixture was furtherheated for 24 hours and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (0-40% EtOAc inhexanes) to yield Intermediate 10 (760 mg, 54%) and Compound 11 (129 mg,11%).

Intermediate 10 ¹H NMR (600 MHz, CD₃OD) δ 8.33 (dd, J=1.17, 4.70 Hz,1H), 7.66 (d, J=7.63 Hz, 1H), 7.60 (dd, J=1.61, 7.78 Hz, 1H), 7.46-7.51(m, 2H), 7.30-7.38 (m, 1H), 7.25 (s, 1H), 7.16-7.22 (m, 2H), 7.09 (dd,J=4.70, 7.92 Hz, 1H), 7.00 (t, J=8.22 Hz, 1H), 6.57 (d, J=7.63 Hz, 1H),4.10 (s, 2H), 1.52 (s, 9H).

Compound 11 ¹H NMR (600 MHz, acetone) δ 8.37 (dd, J=1.47, 4.70 Hz, 1H),7.75 (d, J=7.92 Hz, 1H), 7.48-7.68 (m, 3H), 7.30-7.44 (m, 2H), 7.12 (dd,J=4.70, 7.92 Hz, 1H), 6.87 (t, J=7.63 Hz, 1H), 6.41-6.57 (m, 2H), 6.31(d, J=7.63 Hz, 1H), 4.09 (s, 2H).

EXAMPLE 20 Intermediate 11{3-[3-(benzofuran-2-sulfonylamino)-pyridine-2-sulfinylmethyl]-phenyl}-carbamicacid tert-butyl ester

To a solution of Intermediate 10 (294 mg, 0.58 mmol) in CH₂Cl₂ (5 ml)was added mCPBA (115 mg, 0.58 mmol) and the reaction was stirred at 0°C. for 30 mins and was concentrated. The residue was purified by flashcolumn chromatography on silica gel (100% EtOAc) to yield Intermediate11 (242 mg, 80%).

¹H NMR (600 MHz, CD₃OD) δ 8.84 (br. s., 1H), 8.43 (dd, J=1.17, 4.40 Hz,1H), 7.85 (dd, J=1.03, 8.07 Hz, 1H), 7.73 (d, J=7.92 Hz, 1H), 7.57 (d,J=8.51 Hz, 1H), 7.47-7.52 (m, 2H), 7.45 (dd, J=4.55, 8.36 Hz, 1H), 7.35(t, J=7.63 Hz, 1H), 7.26 (d, J=7.92 Hz, 1H), 7.22 (s, 1H), 7.10 (t,J=7.78 Hz, 1H), 6.70 (d, J=7.63 Hz, 1H), 4.27-4.33 (d, J=12.91 Hz, 1H),4.18-4.23 (d, J=12.91 Hz, 1H), 1.51 (s, 9H).

EXAMPLE 21 Compound 12N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

Intermediate 11 (240 mg, 0.455 mmol), TFA (1 ml) in CH₂Cl₂ (5 ml) wasstirred overnight. The solvent was removed and the crude was purified bycolumn chromatography (50% ethyl acetate in hexanes) to afford Compound12 (186 mg, 96%).

¹H NMR (600 MHz, CD₃OD) δ 8.41 (dd, J=1.32, 4.55 Hz, 1H), 7.82 (dd,J=1.17, 8.51 Hz, 1H), 7.71 (d, J=7.92 Hz, 1H), 7.41-7.57 (m, 4H), 7.33(t, J=7.48 Hz, 1H), 7.14 (t, J=7.78 Hz, 1H), 6.93 (dd, J=1.47, 7.92 Hz,1H), 6.90 (s, 1H), 6.72 (d, J=7.63 Hz, 1H), 4.33 (d, J=13.21 Hz, 1H),4.23 (d, J=13.21 Hz, 1H).

EXAMPLE 22 Compound 13 tert-butyl{3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]phenyl}carbamate

To a solution of Intermediate 10 (418 mg, 0.82 mmol) in CH₂Cl₂ (10 ml)was added mCPBA (426 mg, 2.13 mmol) and the reaction was stirred at roomtemperature for 3 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 13 (340 mg, 76%).

¹H NMR (600 MHz, CD₃OD) δ 8.80 (br. s., 1H), 8.46 (br. s., 1H), 8.15(dd, J=1.32, 8.66 Hz, 1H), 7.73 (d, J=7.92 Hz, 1H), 7.61 (dd, J=4.40,8.22 Hz, 1H), 7.44-7.57 (m, 3H), 7.35 (t, J=7.63 Hz, 1H), 7.25 (s, 1H),7.14 (d, J=7.04 Hz, 1H), 7.00 (t, J=7.92 Hz, 1H), 6.70 (d, J=7.63 Hz,1H), 4.65 (br. s., 2H), 1.50 (s, 9H).

EXAMPLE 23 Compound 14N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

Compound 13 (287 mg, 0.53 mmol), TFA (1 ml) in CH₂Cl₂ (5 ml) was stirredovernight. The solvent was removed and the crude was purified by columnchromatography (50% ethyl acetate) to afford Compound 14 (214 mg, 91%).¹H NMR (600 MHz, CD₃OD) δ 8.46 (d, J=4.40 Hz, 1H), 8.18 (d, J=8.80 Hz,1H), 7.74 (d, J=7.92 Hz, 1H), 7.60-7.67 (m, 1H), 7.54-7.59 (m, 2H),7.47-7.53 (m, 1H), 7.36 (t, J=7.48 Hz, 1H), 6.85-6.96 (m, 1H), 6.55-6.71(m, 2H), 6.42-6.53 (m, 1H), 4.61 (d, J=3.81 Hz, 2H).

EXAMPLE 24 Intermediate 12 2-chloro-5-fluoro-3-nitropyridine

To a solution of 5-fluoro-3-nitro-pyridin-2-ol (2.0 g, 12.65 mmol),benzyltrimethylammonium chloride (1.2 g, 6.33 mmol) in CH₃CN (20 ml) wasadded POCl₃ (5 ml) and the mixture was heated at 80° C. overnight.Another 2 ml POCl₃ was added to the mixture and the reaction was heatedat 80° C. for another 2 hours more. The reaction mixture was quenchedwith water and extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ anhydrous and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (0˜30% EtOAc inhexane) to give Intermediate 12 (1.3 g, 59%).

¹H NMR (600 MHz, CDCl₃) δ 8.55 (d, J=2.64 Hz, 1H), 8.03 (dd, J=2.79,6.60 Hz, 1H).

EXAMPLE 25 Intermediate 13 5-fluoro-3-nitropyridine-2-thiol

To a solution of Intermediate 12 (460 mg, 2.61 mmol) in dioxane (5 ml)and water (1 ml) was added Na₂S.9H₂O and the reaction was stirred at rtfor 5 hours. The reaction was quenched with 1N HCl and then extractedwith EtOAc (2×30 ml). The organic layer was washed with water, brine anddried over Na₂SO₄ and concentrated in vacuo. The crude product was usedin the next reaction without further purification.

EXAMPLE 26 Intermediate 14 2-(benzylthio)-5-fluoro-3-nitropyridine

To the crude Intermediate 13 in DMF (10 ml) was added(bromomethyl)benzene (477 mg, 2.61 mmol) and K₂CO₃ (1.8 g, 13.07 mmol)and the reaction was stirred at room temperature for 16 hours. Thereaction mixture was poured into water (50 ml) and extracted with ethylacetate (2×50 ml). The organic layer was washed with brine and thendried over Na₂SO₄, concentrated in vacuo and purified by flash columnchromatography on silica gel (0˜30% ethyl acetate in hexane) to giveIntermediate 14 (420 mg, 22%).

¹H NMR (600 MHz, CDCl₃) δ 8.66 (d, J=2.64 Hz, 1H), 8.27 (dd, J=2.64,7.63 Hz, 1H), 7.41 (d, J=7.63 Hz, 2H), 7.31 (t, J=7.48 Hz, 2H),7.22-7.28 (m, 1H), 4.45 (s, 2H).

EXAMPLE 27 Intermediate 15 2-(benzylthio)-5-fluoropyridin-3-amine

To a solution Intermediate 14 (420 mg, 1.60 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (2.5 g, 40 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,and the filtrate was extracted with EtOAc (×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 15 (288 mg, 77%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, CD₃OD) δ 7.69 (d, J=2.35 Hz, 1H), 7.11-7.30 (m, 5H),6.77 (dd, J=2.64, 10.27 Hz, 1H), 4.25 (s, 2H).

EXAMPLE 28 Compound 15N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 15 (285 mg, 1.22 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (264 mg, 1.82 mmol) and the reaction wasstirred at 100° C. for 16 hours, then additional benzofuran-2-sulfonylchloride (264 mg, 1.82 mmol) was added and the reaction was furtherheated for 3 hours and concentrated in vacuo. The crude product waspurified by flash column chromatography on silica gel (0-30% EtOAc inhexanes) to yield Compound 15 (379 mg, 75%).

¹H NMR (600 MHz, CD₃OD) δ 8.29 (d, J=2.64 Hz, 1H), 7.71 (d, J=7.92 Hz,1H), 7.45-7.58 (m, 3H), 7.38 (ddd, J=2.93, 4.99, 7.92 Hz, 1H), 7.32 (s,1H), 7.04-7.15 (m, 3H), 6.93 (dd, J=1.32, 7.48 Hz, 2H), 4.10 (s, 2H).

EXAMPLE 29 Compound 16N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 15 (110 mg, 0.27 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (53 mg, 0.27 mmol) and the reaction was stirred at 0° C. for30 min and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 16 (170 mg,72%).

¹H NMR (600 MHz, CD₃OD) δ 8.05 (br. s., 1H), 7.67-7.77 (m, 2H),7.45-7.52 (m, 2H), 7.39-7.45 (m, 1H), 7.27-7.36 (m, 1H), 7.08-7.17 (m,3H), 6.96-7.04 (m, 2H), 4.47 (d, J=12.91 Hz, 1H), 4.26 (d, J=13.21 Hz,1H).

EXAMPLE 30 Compound 17N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 15 (167 mg, 0.40 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (203 mg, 1.01 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 17 (127 mg, 71%).

¹H NMR (600 MHz, CD₃OD) δ 8.35 (d, J=2.35 Hz, 1H), 7.95 (dd, J=2.35,10.56 Hz, 1H), 7.75 (d, J=7.92 Hz, 1H), 7.62 (d, J=0.88 Hz, 1H),7.47-7.57 (m, 2H), 7.38 (td, J=1.17, 7.48 Hz, 1H), 7.05-7.14 (m, 4H),6.98-7.03 (m, 1H), 4.71 (s, 2H).

EXAMPLE 31 Intermediate 16 tert-butyl(3-(((5-chloro-3-nitropyridin-2-yl)thio)methyl)phenyl)carbamate

To Intermediate 1 (590 mg, 3.10 mmol) in DMF (10 ml) was addedtert-butyl (3-(bromomethyl)phenyl)carbamate (889 mg, 2.61 mmol) andK₂CO₃ (2.1 g, 15.53 mmol) and the reaction was stirred at roomtemperature for 3 hours. The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (2×50 ml). The organic layer waswashed with brine and then dried over Na₂SO₄, concentrated in vacuo andpurified by flash column chromatography on silica gel (0˜30% ethylacetate in hexane) to give Intermediate 16 (1.06 g, 88%).

¹H NMR (600 MHz, acetone) δ 8.87 (d, J=2.05 Hz, 1H), 8.64 (d, J=2.35 Hz,1H), 8.35 (br. s., 1H), 7.72 (s, 1H), 7.41 (d, J=8.22 Hz, 1H), 7.21 (t,J=7.92 Hz, 1H), 7.08 (d, J=7.63 Hz, 1H), 4.47 (s, 2H), 1.47 (s, 9H).

EXAMPLE 32 Intermediate 17 tert-butyl(3-(((3-amino-5-chloropyridin-2-yl)thio)methyl)phenyl)carbamate

To a solution Intermediate 16 (1.06 g, 2.68 mmol) in MeOH (30 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (4.3 g, 67 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,and the filtrate was extracted with EtOAc (×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. TheIntermediate 17 (581 mg, 59%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CD₃OD) δ 7.74 (d, J=2.05 Hz, 1H), 7.38 (s, 1H), 7.22(d, J=7.92 Hz, 1H), 7.08 (t, J=7.92 Hz, 1H), 6.92 (d, J=1.76 Hz, 1H),6.89 (d, J=7.63 Hz, 1H), 4.23 (s, 2H), 1.46 (s, 9H).

EXAMPLE 33 Intermediate 18{3-[3-(Benzofuran-2-sulfonylamino)-5-chloro-pyridin-2-ylsulfanylmethyl]-phenyl}-carbamicacid tert-butyl ester

To Intermediate 17 (580 mg, 1.59 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (242 mg, 1.82 mmol) and the reaction wasstirred at 100° C. for 16 hours, then additional benzofuran-2-sulfonylchloride (342 mg, 1.82 mmol) was added and the reaction was furtherheated for 24 hours and concentrated in vacuo. The crude Intermediate 18was purified by flash column chromatography on silica gel (0-30% EtOAcin hexanes) to yield (359 mg, 41%).

¹H NMR (600 MHz, CD₃OD) δ 7.81-7.90 (m, 1H), 7.66 (d, J=7.63 Hz, 1H),7.60 (dd, J=1.61, 7.78 Hz, 1H), 7.40-7.52 (m, 3H), 7.29-7.37 (m, 1H),7.18 (s, 1H), 7.06-7.12 (m, 1H), 7.00 (t, J=8.22 Hz, 1H), 6.57 (d,J=7.63 Hz, 1H), 4.10 (s, 2H), 1.52 (s, 9H).

EXAMPLE 34 Compound 18 Benzofuran-2-sulfonic acid[2-(3-amino-benzylsulfanyl)-5-chloro-pyridin-3-yl]-amide

Intermediate 18 (50 mg, 0.092 mmol), TFA (0.5 ml) in CH₂Cl₂ (5 ml) wasstirred for 2 hours. The solvent was removed and the crude was purifiedby flash column chromatography on silica gel (50% ethyl acetate) toafford Compound 18 (40 mg, 97%).

¹H NMR (600 MHz, CD₃OD) δ 8.34 (d, J=2.05 Hz, 1H), 7.69 (d, J=7.92 Hz,1H), 7.61-7.65 (m, 1H), 7.46-7.56 (m, 2H), 7.36 (td, J=1.03, 7.26 Hz,1H), 7.32 (s, 1H), 7.13 (t, J=7.92 Hz, 1H), 7.04 (s, 1H), 6.97 (dt,J=1.03, 7.92 Hz, 1H), 6.78 (d, J=7.63 Hz, 1H), 4.16 (s, 2H).

EXAMPLE 35 Intermediate 19{3-[3-(benzofuran-2-sulfonylamino)-5-chloro-pyridine-2-sulfinylmethyl]-phenyl}-carbamicacid tert-butyl ester

To a solution of Intermediate 18 (133 mg, 0.24 mmol) in CH₂Cl₂ (5 ml)was added mCPBA (49 mg, 0.24 mmol) and the reaction was stirred at 0° C.for 30 min and was concentrated. The residue was purified by flashcolumn chromatography on silica gel (100% EtOAc) to yield Intermediate19 (80 mg, 58%).

¹H NMR (600 MHz, CD₃OD) δ 7.91 (d, J=1.47 Hz, 2H), 7.68 (d, J=7.92 Hz,1H), 7.42 (d, J=8.22 Hz, 1H), 7.32-7.39 (m, 2H), 7.17-7.31 (m, 3H), 7.00(t, J=7.78 Hz, 1H), 6.66 (d, J=7.63 Hz, 1H), 4.55 (d, J=12.91 Hz, 1H),4.23 (d, J=12.91 Hz, 1H), 1.47 (s, 9H).

EXAMPLE 36 Compound 19N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide

Intermediate 19 (80 mg, 0.15 mmol), TFA (0.5 ml) in CH₂Cl₂ (5 ml) wasstirred for 2 hours. The solvent was removed and the crude was purifiedby flash column chromatography on silica gel (50% ethyl acetate) toafford Compound 19 (60 mg, 91%).

¹H NMR (600 MHz, CD₃OD) δ 8.23 (s, 1H), 7.86 (d, J=1.76 Hz, 1H), 7.72(d, J=7.92 Hz, 1H), 7.48-7.53 (m, 2H), 7.41-7.47 (m, 1H), 7.28-7.37 (m,1H), 7.17-7.25 (m, 1H), 7.03-7.11 (m, 2H), 6.85 (d, J=7.92 Hz, 1H), 4.43(d, J=13.21 Hz, 1H), 4.27 (d, J=13.21 Hz, 1H).

EXAMPLE 37 Intermediate 20{3-[3-(benzofuran-2-sulfonylamino)-5-chloro-pyridine-2-sulfonylmethyl]-phenyl}-carbamicacid tert-butyl ester

To a solution of Intermediate 19 (167 mg, 0.31 mmol) in CH₂Cl₂ (5 ml)was added mCPBA (153 mg, 0.77 mmol) and the reaction was stirred at roomtemperature for 3 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldIntermediate 20 (138 mg, 78%).

¹H NMR (600 MHz, CD₃OD) δ 8.45 (d, J=1.76 Hz, 1H), 8.12 (d, J=2.05 Hz,1H), 7.72 (d, J=7.92 Hz, 1H), 7.56 (s, 1H), 7.44-7.53 (m, 2H), 7.29-7.38(m, 1H), 7.20 (s, 1H), 6.95-7.06 (m, 2H), 6.77 (d, J=6.75 Hz, 1H), 4.63(s, 2H), 1.48 (s, 9H).

EXAMPLE 38 Compound 20N-(2-((3-aminobenzyl)sulfonyl)-5-chloropyridin-3-yl)benzofuran-2-sulfonamide

Intermediate 19 (138 mg, 0.24 mmol), TFA (0.5 ml) in CH₂Cl₂ (5 ml) wasstirred for 2 hours. The solvent was removed and the crude was purifiedby flash column chromatography on silica gel (50% ethyl acetate) toafford Compound 20 (112 mg, 100%).

¹H NMR (600 MHz, CD₃OD) δ 8.29 (d, J=1.76 Hz, 1H), 8.15 (d, J=2.05 Hz,1H), 7.70 (d, J=7.92 Hz, 1H), 7.57 (s, 1H), 7.47-7.51 (m, 1H), 7.42-7.46(m, 1H), 7.28-7.35 (m, 1H), 7.07-7.18 (m, 2H), 6.97-7.04 (m, 1H), 6.89(d, J=7.63 Hz, 1H), 4.77 (s, 2H).

EXAMPLE 39 Intermediate 21 5-methyl-3-nitropyridine-2-thiol

To a solution of 2-chloro-5-methyl-3-nitropyridine (1 g, 5.80 mmol) indioxane (5 ml) and water (1 ml) was added Na₂S.9H₂O (1.39 g, 5.80 mmol)and the reaction was stirred at rt for 3 hours. The reaction wasquenched with 1N HCl and then extracted with EtOAc (2×30 ml). Theorganic layer was washed with water, brine and dried over Na₂SO₄anhydride and concentrated in vacuo.

EXAMPLE 40 Intermediate 22 2-(benzylthio)-5-methyl-3-nitropyridine

To the crude Intermediate 21 in DMF (10 ml) was added(bromomethyl)benzene (991 mg, 5.80 mmol) and K₂CO₃ (2.4 g, 17.39 mmol)and the reaction was stirred at room temperature for 16 hours. Thereaction mixture was poured into water (50 ml) and extracted with ethylacetate (2×50 ml). The organic layer was washed with brine and thendried over Na₂SO₄, concentrated in vacuo and purified by flash columnchromatography on silica gel (0˜30% ethyl acetate in hexane) to giveIntermediate 22 (660 mg, 44%).

¹H NMR (600 MHz, acetone) δ 8.71 (d, J=0.88 Hz, 1H), 8.42 (d, J=0.59 Hz,1H), 7.45 (d, J=7.34 Hz, 2H), 7.30 (t, J=7.63 Hz, 2H), 7.21-7.26 (m,J=7.34 Hz, 1H), 4.49 (s, 2H), 2.45 (s, 3H).

EXAMPLE 41 Intermediate 23 2-(benzylthio)-5-methylpyridin-3-amine

To a solution of Intermediate 22 (660 mg, 2.55 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (4.1 g, 63.71 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 23 (512 mg, 88%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, acetone) δ 7.72 (s, 1H), 7.38 (d, J=7.34 Hz, 2H), 7.26(t, J=7.48 Hz, 2H), 7.18-7.22 (m, 1H), 6.81 (s, 1H), 4.53 (br. s., 2H),4.42 (s, 2H), 2.16 (s, 3H).

EXAMPLE 42 Compound 21N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 23 (510 mg, 2.23 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (481 mg, 2.23 mmol) and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 21 (466 mg, 51%).

¹H NMR (600 MHz, acetone) δ 9.03 (br.s, 1H), 8.24 (d, J=0.88 Hz, 1H),7.73-7.78 (m, 1H), 7.53-7.62 (m, 2H), 7.49-7.51 (m, 1H), 7.39-7.43 (m,1H), 7.37 (s, 1H), 7.11-7.20 (m, 3H), 7.04 (dd, J=2.79, 6.60 Hz, 2H),4.17 (s, 2H), 2.28 (s, 3H).

EXAMPLE 43 Compound 22N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 21 (143 mg, 0.349 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (70 mg, 0.349 mmol) and the reaction was stirred at roomtemperature for 3 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 22 (129 mg, 85%).

¹H NMR (600 MHz, acetone) δ 11.12 (br. s., 1H), 8.16 (d, J=1.17 Hz, 1H),7.85 (d, J=0.88 Hz, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H),7.47-7.54 (m, 1H), 7.37 (t, J=7.63 Hz, 1H), 7.12-7.26 (m, 3H), 6.98-7.08(m, 2H), 4.35 (d, J=13.21 Hz, 1H), 4.21 (d, J=13.21 Hz, 1H), 2.36 (s,3H).

EXAMPLE 44 Compound 23N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 21 (241 mg, 0.588 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (291 mg, 1.47 mmol) and the reaction was stirred at roomtemperature for 3 hours, and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 23 (203 mg, 78%).

¹H NMR (600 MHz, acetone) δ 8.34 (d, J=0.59 Hz, 1H), 7.99 (s, 1H), 7.76(d, J=7.92 Hz, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.51 (td, J=1.03, 7.85Hz, 1H), 7.35 (t, J=7.63 Hz, 1H), 7.11-7.24 (m, 5H), 4.75 (s, 2H), 2.40(s, 3H).

EXAMPLE 45 Intermediate 245-chloro-2-((2-methylpyridin-3-yl)oxy)-3-nitropyridine

To a solution of 2,5-dichloro-3-nitropyridine (655 mg, 3.41 mmol) in DMF(10 ml) was added 2-methylpyridin-3-ol (368 mg, 3.41 mmol) and K₂CO₃(2.35 g, 17.05 mmol) and the reaction was stirred at 90° C. for 3 hours,diluted with H₂O, and the resulting solution was extracted with EtOAc.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo, followed by MPLC purification to yieldIntermediate 24 as yellow solid (705 mg, 78%).

¹H NMR (600 MHz, acetone) δ 8.61-8.68 (m, 1H), 8.34-8.46 (m, 2H), 7.61(d, J=8.22 Hz, 1H), 7.14-7.46 (m, 1H), 2.37 (s, 3H).

EXAMPLE 46 Intermediate 255-chloro-2-((2-methylpyridin-3-yl)oxy)pyridin-3-amine

To a solution of Intermediate 24 (705 mg, 2.92 mmol) in MeOH (15 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (4.7 g, 73 mmol). Thesuspension was stirred at room temperature for 0.5 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 25 (476 mg, 76%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, acetone) δ 8.31 (d, J=4.40 Hz, 1H), 7.45 (d, J=7.92 Hz,1H), 7.21-7.28 (m, 2H), 7.16 (d, J=2.05 Hz, 1H), 5.26 (br. s., 2H), 2.33(s, 3H).

EXAMPLE 47 Compound 24N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To Intermediate 25 (476 mg, 2.0 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (437 mg, 2.0 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) followed by re-crystallization from20% EtOAc/Hexane to yield Compound 24 (419 mg, 50%) as a yellow solid.

¹H NMR (600 MHz, CD₃OD) δ 8.18 (dd, J=1.32, 4.84 Hz, 1H), 8.02 (dd,J=1.03, 2.49 Hz, 1H), 7.79-7.83 (m, 1H), 7.73 (d, J=7.92 Hz, 1H),7.45-7.53 (m, 3H), 7.33-7.40 (m, 1H), 7.10 (dd, J=4.99, 8.22 Hz, 1H),6.94 (d, J=9.39 Hz, 1H), 1.99 (s, 3H).

EXAMPLE 48 Intermediate 26 methyl2-((5-chloro-3-nitropyridin-2-yl)oxy)benzoate

To a solution of 2,5-dichloro-3-nitropyridine (1 g, 5.2 mmol) in DMF (10ml) was added methyl 2-hydroxybenzoate (790 mg, 5.2 mmol) and K₂CO₃ (3.6g, 25.9 mmol) and the reaction was stirred at 90° C. for 3 hours,diluted with H₂O, and the resulting solution was extracted with EtOAc.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo, followed by MPLC purification to yieldIntermediate 26 as clear oil (1.5 g, 93%).

¹H NMR (600 MHz, acetone) δ 8.59-8.64 (m, 1H), 8.32 (d, J=1.76 Hz, 1H),8.05 (dd, J=1.61, 7.78 Hz, 1H), 7.72-7.78 (m, 1H), 7.45-7.50 (m, 1H),7.40 (d, J=8.22 Hz, 1H), 3.65 (s, 3H).

EXAMPLE 49 Intermediate 27 methyl2-((3-amino-5-chloropyridin-2-yl)oxy)benzoate

To a solution of Intermediate 26 (1.5 mg, 4.82 mmol) in MeOH (30 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (7.8 g, 121 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, and the filtrate was extracted with EtOAc (×2). The organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude Intermediate 27 (1.12 g, 83%) was used in the nextreaction without further purification.

¹H NMR (600 MHz, acetone) δ 7.92 (dd, J=1.47, 7.92 Hz, 1H), 7.57-7.69(m, 1H), 7.28-7.38 (m, 2H), 7.19 (d, J=1.76 Hz, 1H), 7.12 (dd, J=0.59,2.35 Hz, 1H), 5.18 (br. s., 2H), 3.66 (s, 3H).

EXAMPLE 50 Compound 25 methyl2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate

To Intermediate 27 (413 mg, 1.5 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (320 mg, 1.5 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) to yield Compound 25 (627 mg, 92%)as a yellow solid.

¹H NMR (600 MHz, CD₃OD) δ 8.00 (d, J=2.35 Hz, 1H), 7.89 (dd, J=1.32,7.78 Hz, 1H), 7.75 (d, J=7.92 Hz, 1H), 7.71 (d, J=2.35 Hz, 1H),7.47-7.55 (m, 3H), 7.35-7.41 (m, J=7.63 Hz, 2H), 7.26 (t, J=7.63 Hz,1H), 6.52 (d, J=8.22 Hz, 1H), 3.47 (s, 3H).

EXAMPLE 51 Compound 262-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoicacid

To Compound 25 (627 mg, 1.36 mmol) in MeOH (30 ml) was added NaOH (5N, 2ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 26 (485 mg, 80%).

¹H NMR (600 MHz, acetone) δ 11.22 (br. s., 1H), 9.66 (br. s., 1H),7.96-8.01 (m, 2H), 7.81 (d, J=7.92 Hz, 1H), 7.77 (d, J=2.35 Hz, 1H),7.65 (s, 1H), 7.58-7.61 (m, 1H), 7.54 (ddd, J=1.17, 7.26, 8.29 Hz, 1H),7.49 (td, J=1.61, 7.70 Hz, 1H), 7.38-7.43 (m, 1H), 7.32 (t, J=7.63 Hz,1H), 6.80 (d, J=7.92 Hz, 1H).

EXAMPLE 52 Intermediate 28(3-amino-5-chloropyridin-2-yl)(morpholino)methanone

A solution of 3-amino-5-chloropicolinic acid hydrogen chloride (226 mg,1.08 mmol), morpholine (94 μl, 1.08 mmol), EDCI (308 mg, 1.61 mmol) andDMAP (394 mg, 3.23 mmol) in CH₂Cl₂ (5 ml) was stirred at roomtemperature overnight, diluted with H₂O, and the resulting solution wasextracted with CH₂Cl₂. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo, followed by MPLC purification toyield Intermediate 28 as a yellow oil (173 mg, 66%).

¹H NMR (600 MHz, acetone) δ 7.80 (d, J=2.35 Hz, 1H), 7.28 (d, J=2.35 Hz,1H), 5.78 (br. s., 2H), 3.83-4.04 (m, 4H), 2.51 (d, J=4.40 Hz, 4H).

EXAMPLE 53 Compound 27N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 28 (170 mg, 0.70 mmol) in pyridine (3 ml) was addedbenzofuran-2-sulfonyl chloride (152 mg, 0.70 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) to yield Compound 27 (78 mg, 26%).

¹H NMR (600 MHz, acetone) δ 7.85-7.94 (m, 1H), 7.71 (d, J=2.05 Hz, 1H),7.64 (d, J=8.22 Hz, 1H), 7.46 (d, J=8.22 Hz, 1H), 7.33 (ddd, J=1.17,7.26, 8.29 Hz, 1H), 7.20-7.27 (m, 1H), 7.14 (d, J=0.59 Hz, 1H), 3.67 (s,4H), 3.47-3.57 (m, 2H), 3.09-3.18 (m, 2H).

EXAMPLE 54 Intermediate 29 1-(3-amino-5-chloropicolinoyl)piperidin-4-one

A solution of 3-amino-5-chloropicolinic acid hydrogen chloride (303 mg,1.44 mmol), piperidin-4-one (220 mg, 1.44 mmol), EDCI (413 mg, 2.16mmol) and DMAP (528 mg, 4.33 mmol) in CH₂Cl₂ (5 ml) was stirred at roomtemperature overnight, diluted with H₂O, and the resulting solution wasextracted with CH₂Cl₂. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo, followed by MPLC purification toyield Intermediate 29 (255 mg, 79%).

¹H NMR (600 MHz, acetone) δ 7.80 (s, 1H), 7.28 (d, J=2.35 Hz, 1H), 5.78(br. s., 2H), 3.72-4.13 (m, 4H), 2.51 (d, J=4.40 Hz, 4H).

EXAMPLE 55 Compound 28N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To Intermediate 29 (288 mg, 1.13 mmol) in pyridine (3 ml) was addedbenzofuran-2-sulfonyl chloride (245 mg, 1.13 mmol) and the reaction wasstirred at room temperature for 16 hours. Solvent was removed in vacuoand the crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) to yield Compound 28 (52 mg, 10%).

¹H NMR (300 MHz, CDCl₃) δ 8.24 (d, J=2.05 Hz, 1H), 8.14 (d, J=2.05 Hz,1H), 7.65 (d, J=7.62 Hz, 1H), 7.42-7.55 (m, 2H), 7.29-7.41 (m, 2H), 3.86(t, J=6.15 Hz, 2H), 3.51 (t, J=6.15 Hz, 2H), 2.50 (t, J=6.30 Hz, 2H),2.36 (t, J=5.86 Hz, 2H).

EXAMPLE 56 Intermediate 30 5-chloro-3-nitropicolinic acid

To a suspension of4-(5-chloro-3-nitropyridin-2-yl)-2-methylbut-3-yn-2-ol (2.1 g, 8.71mmol) in H₂O (30 ml) was added KMnO₄ (4.55 g, 28.78 mmol) portion wiseover 30 min at 75° C. After addition, the reaction was stirred at 75° C.for 2 hours, then cooled down to room temperature and adjusted pH to ˜9by addition of 1N NaOH and filtered away the solid. The filtrate wasdiluted with H₂O, and extracted with EtOAc and discarded. The aqueousportion was acidified to pH 2-3 with 1N HCl, the resulting solution wasextracted with EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to yield Intermediate 30 as yellow solid (1.23 g,71%).

¹H NMR (300 MHz, acetone) δ 8.98 (d, J=2.05 Hz, 1H), 8.67 (d, J=2.05 Hz,1H).

EXAMPLE 57 Intermediate 31(5-chloro-3-nitropyridin-2-yl)(phenyl)methanone

To a solution of Intermediate 30 (724 mg, 3.62 mmol) in CH₂Cl₂ (5 ml)was added oxalyl chloride (3.6 ml, 7.24 mmol) at room temperaturefollowed by a drop of DMF. After stirring for 1.5 hours, the mixture wasconcentrated and dried under high vacuum. The crude acid chloride wasdissolved in benzene (30 ml) and AlCl₃ (499 mg, 3.75 mmol) was added.The resulting mixture was heated at 80° C. for 3.5 hours. The reactionwas quenched with NaHCO₃ and extracted with EtOAc (×2). The organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by flash column chromatography onsilica gel (0-30% EtOAc in hexanes) to yield Intermediate 31 (675 mg,72%).

¹H NMR (300 MHz, acetone) δ 9.05 (d, J=2.34 Hz, 1H), 8.83 (d, J=2.05 Hz,1H), 7.85-7.99 (m, 2H), 7.66-7.80 (m, 1H), 7.48-7.64 (m, 2H).

EXAMPLE 58 Intermediate 32(3-amino-5-chloropyridin-2-yl)(phenyl)methanone

To a solution of Intermediate 31 (477 mg, 1.84 mmol) in EtOH (10 ml) wasadded SnCl₂ (1.95 g, 10.28 mmol). The mixture was stirred at 80° C. for2 days. The solvent was removed, NaOH (1N) was added to adjusted the pH˜11. The cloud mixture was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(0-30% EtOAc in hexanes) to yield Intermediate 32 (308 mg, 73%).

¹H NMR (300 MHz, acetone) δ 7.89-7.97 (m, 1H), 7.87 (d, J=2.05 Hz, 1H),7.38-7.61 (m, 3H), 7.04-7.24 (m, 2H).

EXAMPLE 59 Compound 29N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 32 (300 mg, 1.29 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (288 mg, 1.29 mmol) and DMAP (cat.) andthe reaction was stirred at 100° C. for 16 hours. Solvent was removed invacuo and the crude product was purified by flash column chromatographyon silica gel (0-30% EtOAc in hexanes) and further purified bypreparative TLC to yield Compound 29 (118 mg, 22%).

¹H NMR (300 MHz, acetone) δ 8.46 (d, J=2.05 Hz, 1H), 8.28 (d, J=2.05 Hz,1H), 7.71-7.83 (m, 4H), 7.54-7.63 (m, 1H), 7.28-7.50 (m, 5H).

EXAMPLE 60 Intermediate 33 5-chloro-3-nitro-2-(phenylthio)pyridine

To a solution of 2,5-dichloro-3-nitropyridine (995 mg, 5.0 mmol) in MeOH(5 ml) was added benzenethiol (0.51 ml, 5.0 mmol) and 4M NaOH (1.25 ml,5.0 mmol) and the reaction was stirred at room temperature for 4 hours,diluted with 1M NaOH, extracted with EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The crude waspurified by flash column chromatography on silica gel (0-5% EtOAc inhexanes) to yield Intermediate 33 as a yellow solid (1.33 g, 100%).

1H NMR (CHLOROFORM-d) δ 8.49 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.3 Hz, 1H),7.51-7.56 (m, 2H), 7.43-7.49 (m, 3H).

EXAMPLE 61 Intermediate 34 5-chloro-2-(phenylthio)pyridin-3-amine

To a solution of Intermediate 33 (0.65 g, 2.43 mmol) in HOAc (10 ml) wasadded iron powder (0.68 g, 12.2 mmol). The suspension was stirred at 70°C. for 1.5 hours and was concentrated, diluted with EtOAc, washed with1M NaOH, brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (10%EtOAc in hexanes) to yield Intermediate 34 as a light brown solid (567mg, 98%).

1H NMR (CHLOROFORM-d) δ: 7.96 (d, J=2.3 Hz, 1H), 7.18-7.32 (m, 5H), 7.02(d, J=2.3 Hz, 1H), 4.27 (br. s., 2H).

EXAMPLE 62 Compound 30N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 34 (551 mg, 2.32 mmol) in pyridine (10 ml) was addedbenzofuran-2-sulfonyl chloride (505 mg, 2.32 mmol) and DMAP (28 mg, 0.23mmol). The reaction was stirred at 100° C. for 12 hours, when additionalbenzofuran-2-sulfonyl chloride (505 mg, 2.32 mmol) was added. Thereaction was continued at 100° C. for 12 hours and was concentrated invacuo. The residue was purified by flash column chromatography on silicagel (10-30% EtOAc in hexanes) to yield Compound 30 as a light brownsolid (271 mg, 28%).

1H NMR (CHLOROFORM-d) δ: 8.23 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H),7.70 (br. s., 1H), 7.66 (dt, J=7.8, 1.1 Hz, 1H), 7.46-7.50 (m, 2H), 7.40(s, 1H), 7.31-7.38 (m, 1H), 7.09-7.23 (m, 5H).

EXAMPLE 63 Compound 31N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 30 (200 mg, 0.48 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (173 mg, ˜0.72 mmol) and the reaction was stirred at roomtemperature for 2 hours and additional mCPBA (58 mg, ˜0.24 mmol) wasadded. The reaction was continued for 1 hour and was diluted withsaturated aqueous NaHCO₃ and saturated aqueous Na₂CO₃ to ˜pH8, extractedwith EtOAc (×3). The combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (50-100% EtOAc in hexanesfollowed by 5% MeOH in EtOAc) to yield Compound 31 (119 mg, 55%).

1H NMR (METHANOL-d4) δ: 8.23 (d, J=2.1 Hz, 1H), 8.19 (s, 1H), 7.82 (dd,J=8.4, 1.0 Hz, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.45-7.58 (m, 4H), 7.29-7.40(m, 3H).

EXAMPLE 64 Compound 32N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 30 (200 mg, 0.48 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (173 mg, ˜0.72 mmol) and the reaction was stirred at roomtemperature for 2 hours and additional mCPBA (58 mg, ˜0.24 mmol) wasadded. The reaction was continued for 1 hour and was diluted withsaturated aqueous NaHCO₃ and saturated aqueous Na₂CO₃ to ˜pH8, extractedwith EtOAc (×3). The combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (50-100% EtOAc in hexanesfollowed by 5% MeOH in EtOAc) to yield Compound 32 (73 mg, 35%).

1H NMR (METHANOL-d4) δ: 8.03 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.70-7.76(m, 2H), 7.60 (dt, J=7.8, 0.9 Hz, 1H), 7.35-7.39 (m, 2H), 7.21-7.29 (m,4H), 7.01 (s, 1H).

EXAMPLE 65 Intermediate 355-chloro-2-((2-methylpyridin-3-yl)methoxy)-3-nitropyridine

To a solution of 5-chloro-2-fluoro-3-nitropyridine (520 mg, 2.96 mmol)in DMF (10 ml) was added (2-methylpyridin-3-yl)methanol (364 mg, 2.96mmol) and K₂CO₃ (2.00 g, 14.82 mmol) and the reaction was stirred atroom temperature for 16 hours, diluted with H₂O, and the resultingsolution was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo, followed by MPLCpurification to yield Intermediate 36 as a yellow solid (500 mg, 61%).

¹H NMR (600 MHz, CD₃OD) δ 8.32-8.44 (m, 1H), 7.87-7.98 (m, 2H), 7.65(dd, J=2.64, 9.10 Hz, 1H), 7.46 (d, J=9.10 Hz, 1H), 5.31 (s, 2H), 2.58(s, 3H).

EXAMPLE 66 Intermediate 365-chloro-2-((2-methylpyridin-3-yl)methoxy)pyridine-3-amine

To a solution of Intermediate 35 (490 mg, 1.76 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (2.9 g, 44 mmol). Thesuspension was stirred at room temperature for 1 hour and was filtered,and the filtrate was extracted with EtOAc (×2). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. TheIntermediate 36 (439 mg, 100%) was used in the next reaction withoutfurther purification.

¹H NMR (300 MHz, acetone) δ 8.52 (d, J=3.80, 1H), 7.88 (d, J=7.91 Hz,1H), 6.94 (d, J=8.50 Hz, 1H), 6.77 (d, J=2.64 Hz, 1H), 6.56 (dd, J=2.64,8.50 Hz, 1H), 5.16 (s, 2H), 2.62 (s, 3H).

EXAMPLE 67 Compound 33N-{5-chloro-2-[(2-methylpyridin-3-yl)methoxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide

To Intermediate 37 (439 mg, 1.77 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (382 mg, 1.77 mmol) and the reaction wasstirred at 100° C. for 16 hours. Solvent was removed in vacuo and thecrude product was purified by flash column chromatography on silica gel(0-100% EtOAc in hexanes) to yield Compound 33 (350 mg, 46%) as a yellowsolid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd, J=1.32, 5.71 Hz, 1H), 8.45 (d,J=7.62 Hz, 1H), 7.82 (dd, J=5.71, 7.77 Hz, 1H), 7.60 (d, J=7.62 Hz, 1H),7.33-7.48 (m, 4H), 7.19-7.31 (m, 2H), 4.89 (s, 2H), 2.46 (s, 3H).

EXAMPLE 68 Intermediate 37 2-bromo-5-chloropyridin-3-amine

To a suspension of iron powder (1.3 g, 23.16 mmol) in AcOH (8 ml) at 80°C. was added a solution of 2-bromo-5-chloro-3-nitropyridine (1 g, 4.21mmol) in AcOH (8 ml) via addition funnel and the reaction was stirred at80° C. for 30 min. The reaction was subsequently cooled to roomtemperature, diluted with EtOAc, filtered through a pad of Celtite andconcentrated in vacuo. The residue was dissolved in EtOAc, and washedwith 1N NaOH and brine, dried over Na₂SO₄ and concentrated in vacuo toafford Intermediate 38 (861 mg, 99%) as a yellow solid which was useddirectly without further purification.

¹H NMR (300 MHz, acetone) δ 7.62 (d, J=2.34 Hz, 1H), 7.22 (d, J=2.34 Hz,1H), 5.40 (br. s., 2H).

EXAMPLE 69 Intermediate 38N-(2-bromo-5-chloropyridin-3-yl)benzofuran-2-sulfonamide

To Intermediate 37 (861 mg, 4.16 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (900 mg, 4.16 mmol) and the reaction wasstirred at 100° C. for 16 hours. Solvent was removed in vacuo and thecrude product was purified by flash column chromatography on silica gel(0-100% EtOAc in hexanes) to yield Intermediate 38 (490 mg, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (d, J=2.34 Hz, 1H), 7.86 (d, J=2.34 Hz,1H), 7.73-7.78 (m, 1H), 7.69 (dd, J=0.88, 8.20 Hz, 1H), 7.46-7.56 (m,2H), 7.32-7.41 (m, 1H).

EXAMPLE 70 Intermediate 39N-(2-bromo-5-chloropyridin-3-yl)-N-(methoxymethyl)benzofuran-2-sulfonamide

To a solution of Intermediate 38 (377 mg, 0.974 mmol) in THF (10 ml) at0° C. was added NaH (37 mg, 95%, 1.46 mmol) and further stirred for 30min. Then MOMCI (81 ul, 1.07 mmol) was added into the mixture at 0° C.and further stirred for 1 hour more. Water was added to quenched thereaction, extracted with EtOAc (×2), washed with brine and dried overNa₂SO₄ and concentrated in vacuo. The crude was purified by flash columnchromatography on silica gel (0-30% EtOAc in hexanes) to yieldIntermediate 39 (350 mg, 83%).

¹H NMR (600 MHz, CDCl₃) δ 8.37 (d, J=2.35 Hz, 1H), 7.76 (d, J=2.64 Hz,1H), 7.67 (dt, J=0.99, 7.70 Hz, 1H), 7.59 (dd, J=0.73, 8.36 Hz, 1H),7.51 (ddd, J=1.32, 7.19, 8.51 Hz, 1H), 7.36 (td, J=1.03, 7.56 Hz, 1H),7.31 (d, J=0.88 Hz, 1H), 5.35 (br. s., 1H), 5.01 (br. s., 1H), 3.50 (s,3H).

EXAMPLE 71 Intermediate 40 N-methoxy-N-methyl-2-phenylacetamide

To a mixture of 2-phenylacetyl chloride (1 g, 6.47 mmol) andN,O-dimethylhydroxylamine (757 mg, 7.76 mmol) in CH₂Cl₂ (30 ml) wasadded TEA (2.7 ml, 19.41 mmol) at 0° C. After the reaction was stirredfor 15 min at 0° C., it was warmed up to room temperature for 1 hourunder N₂. The mixture was diluted with H₂O, and the resulting solutionwas extracted with EtOAc and washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to yield Intermediate 40 crude (1.03 g, 85%),which was used without further purification.

¹H NMR (600 MHz, acetone) δ 6.71-7.41 (m, 5H), 3.61 (s, 2H), 3.56 (s,3H), 2.99 (s, 3H).

EXAMPLE 72 Intermediate 41N-(5-chloro-2-(2-phenylacetyl)pyridin-3-yl)-N-(methoxymethyl)benzofuran-2-sulfonamide

To a solution of Intermediate 39 (300 mg, 0.69 mmol) in THF (3 ml) underN₂ at −78° C. was added dropwise of i-PrMgCl (1 ml, 2.08 mmol, 2.0 M inTHF). The reaction was stirred at −78° C. for 10 min, followed bywarming to room temperature for 30 min. The mixture was cooled down to0° C. and a solution of Intermediate 40 (248 mg, 1.39 mmol) in THF (1ml) was added and stirred for 3 hour at room temperature. The mixturewas diluted with H₂O, and the resulting solution was extracted withEtOAc and washed with brine, dried over Na₂SO₄ and concentrated invacuo. The crude Intermediate 41 was purified by flash columnchromatography on silica gel (0-30% EtOAc in hexanes) to yield (69 mg,21%).

¹H NMR (600 MHz, acetone) δ 8.80 (t, J=2.05 Hz, 1H), 7.94-7.98 (m, 1H),7.81 (d, J=7.92 Hz, 1H), 7.65 (d, J=8.51 Hz, 1H), 7.52-7.62 (m, 1H),7.37-7.50 (m, 2H), 7.12-7.27 (m, 3H), 7.02 (d, J=7.63 Hz, 2H), 5.15 (br.s., 2H), 4.29 (br. s., 2H), 3.41 (s, 3H).

EXAMPLE 73 Compound 34N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

The mixture of Intermediate 42 (58 mg, 0.123 mmol) and 4M HCl in dioxane(5 ml) in H₂O (1 ml) was heated at 100° C. for 3 hours. The mixture wascooled down to room temperature, and adjusted the pH to ˜9 by NaHCO₃(sat.), extracted with EtOAc (×2), The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The crude waspurified by flash column chromatography on silica gel (0-30% EtOAc inhexanes) to yield Compound 34 (28 mg, 53%).

¹H NMR (600 MHz, acetone) δ 11.58 (br. s., 1H), 8.32 (d, J=2.05 Hz, 1H),8.09 (d, J=2.05 Hz, 1H), 7.72 (d, J=0.88 Hz, 1H), 7.63-7.68 (m, 1H),7.38-7.46 (m, 2H), 7.25 (ddd, J=1.17, 6.75, 7.92 Hz, 1H), 7.10-7.15 (m,4H), 7.05-7.10 (m, 1H), 4.39 (s, 2H).

EXAMPLE 74 Intermediate 43 methyl2-(((5-chloro-3-nitropyridin-2-yl)thio)methyl)benzoate

To the crude Intermediate 42 in DMF (10 ml) was added methyl2-(bromomethyl)benzoate (1.47 g, 6.44 mmol) and K₂CO₃ (2.7 g, 19.32mmol) and the reaction was stirred at room temperature for 16 hours. Thereaction mixture was poured into water (50 ml) and extracted with ethylacetate (2×50 ml). The organic layer was washed with brine and thendried over Na₂SO₄ anhydride, concentrated in vacuo and purified by flashcolumn chromatography on silica gel (0˜30% ethyl acetate in hexane) togive Intermediate 43 (573 mg, 26%).

¹H NMR (300 MHz, CD₃OD) δ 8.77 (d, J=2.34 Hz, 1H), 8.60 (d, J=2.34 Hz,1H), 7.90 (d, J=7.91 Hz, 1H), 7.64 (d, J=6.74 Hz, 1H), 7.42-7.54 (m,1H), 7.27-7.39 (m, 1H), 4.88 (s, 2H), 3.91 (s, 3H).

EXAMPLE 75 Intermediate 44 methyl2-(((3-amino-5-chloropyridin-2-yl)thio)methyl)benzoate

To a solution of Intermediate 43 (575 mg, 1.70 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (2.8 g, 42.40 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 44 (430 mg, 82%) was used in the next reactionwithout further purification.

¹H NMR (600 MHz, CD₃OD) δ 7.87 (d, J=7.92 Hz, 1H), 7.71-7.79 (m, 1H),7.35-7.43 (m, 2H), 7.30 (t, J=7.34 Hz, 1H), 6.92-7.00 (m, 1H), 4.71 (s,2H), 3.89 (d, J=0.88 Hz, 3H).

EXAMPLE 76 Compound 35 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoate

To Intermediate 44 (430 mg, 1.40 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (300 mg, 1.40 mmol) was added and thereaction was stirred at 100° C. for 16 hours, then additionalbenzofuran-2-sulfonyl chloride (300 mg, 1.40 mmol) and the reaction washeated for another 24 hours and was concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Compound 35 (341 mg, 50%).

¹H NMR (300 MHz, CD₃OD) δ 8.32 (d, J=2.34 Hz, 1H), 7.70-7.81 (m, 1H),7.59-7.67 (m, 2H), 7.40-7.49 (m, 2H), 7.12-7.38 (m, 5H), 4.54 (s, 2H),3.81 (s, 3H).

EXAMPLE 77 Compound 362-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoicacid

To Compound 35 (60 mg, 0.12 mmol) in MeOH (5 ml) was added 5N NaOH (1ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 36 (47 mg, 80%).

¹H NMR (300 MHz, CD₃OD) δ 8.33 (d, J=2.34 Hz, 1H), 7.74-7.85 (m, 1H),7.56-7.69 (m, 2H), 7.46 (d, J=3.52 Hz, 2H), 7.07-7.38 (m, 5H), 4.58 (s,3H).

EXAMPLE 79 Compound 37 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoate

To a solution of Compound 35 (106 mg, 0.22 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (44 mg, 0.22 mmol) and the reaction was stirred at 0° C. for30 mins and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 37 (82 mg,75%).

¹H NMR (300 MHz, CD₃OD) δ 7.86 (d, J=2.05 Hz, 1H), 7.81 (d, J=1.47 Hz,1H), 7.78 (d, J=1.17 Hz, 1H), 7.62-7.72 (m, 1H), 7.41-7.48 (m, 1H),7.21-7.39 (m, 4H), 7.16 (td, J=1.47, 7.47 Hz, 1H), 6.83 (d, J=7.62 Hz,1H), 5.17 (d, J=12.60 Hz, 1H), 4.79 (d, J=12.60 Hz, 1H), 3.84 (s, 3H).

EXAMPLE 80 Compound 38 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoate

To a solution of Compound 35 (88 mg, 0.18 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (90 mg, 0.45 mmol) and the reaction was stirred at roomtemperature for 3 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 38 (55 mg, 59%).

¹H NMR (300 MHz, CD₃OD) δ 8.18 (d, J=2.05 Hz, 1H), 7.83 (d, J=8.20 Hz,1H), 7.62-7.73 (m, 2H), 7.20-7.49 (m, 5H), 6.93-7.09 (m, 2H), 5.67 (s,2H), 3.88 (s, 3H).

EXAMPLE 81 Compound 392-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoicacid

To Compound 38 (55 mg, 0.11 mmol) in MeOH (5 ml) was added 5N NaOH (1ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 39 (36 mg, 43%).

¹H NMR (300 MHz, CD₃OD) δ 8.35 (s, 1H), 8.21 (d, J=1.76 Hz, 1H), 7.82(d, J=7.33 Hz, 1H), 7.78-7.78 (m, 1H), 7.75 (s, 1H), 7.62 (s, 1H),7.48-7.59 (m, 2H), 7.28-7.42 (m, 2H), 7.13-7.27 (m, 2H), 5.40 (s, 2H).

EXAMPLE 82 Intermediate 45 5-fluoro-3-nitro-2-(phenylthio)pyridine

To a solution of 2-bromo-5-fluoro-3-nitropyridine (1.17 g, 5.29 mmol) inDMF (10 ml) was added benzenethiol (0.54 ML, 5.29 mmol) and K₂CO₃ (2.19g, 15.88 mmol), and the reaction was stirred at room temperature for 16hours, diluted with H₂O, and the resulting solution was extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo, followed by MPLC purification to yieldIntermediate 45 as yellow solid.

¹H NMR (300 MHz, CD₃OD) δ 8.42-8.54 (m, 2H), 7.36-7.49 (m, 5H).

EXAMPLE 83 Intermediate 46 5-fluoro-2-(phenylthio)pyridin-3-amine

To a solution of Intermediate 45 (1.3 g, 5.29 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (8.6 g, 132 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 46 (735 mg, 55%, 2-step yield) was used in the nextreaction without further purification.

¹H NMR (300 MHz, CD₃OD) δ 7.72 (d, J=2.64 Hz, 1H), 7.06-7.29 (m, 5H),6.95 (dd, J=2.64, 10.55 Hz, 1H).

EXAMPLE 84 Compound 40N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 46 (735 mg, 3.34 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (735 mg, 3.34 mmol) and the reaction wasstirred at 100° C. for 16 hours. Solvent was removed in vacuo and thecrude product was purified by flash column chromatography on silica gel(0-100% EtOAc in hexanes) to yield Compound 40 (150 mg, 11%).

¹H NMR (300 MHz, CD₃OD) δ 8.12 (d, J=2.64 Hz, 1H), 7.62-7.77 (m, 2H),7.42-7.58 (m, 2H), 7.28-7.41 (m, 2H), 7.06-7.23 (m, 3H), 6.90-7.00 (m,2H).

EXAMPLE 85 Compound 41N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 40 (60 mg, 0.15 mmol) in CH₂Cl₂ (3 ml) wasadded mCPBA (30 mg, 0.15 mmol) and the reaction was stirred at 0° C. for20 min and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 41 (44 mg,73%).

¹H NMR (300 MHz, CD₃OD) δ 8.25 (br. s., 1H), 7.89 (dd, J=1.90, 10.11 Hz,1H), 7.68-7.77 (m, 1H), 7.55-7.64 (m, 3H), 7.41-7.54 (m, 3H), 7.32-7.40(m, 1H), 7.21-7.30 (m, 3H).

EXAMPLE 86 Compound 42N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 40 (57 mg, 0.13 mmol) in CH₂Cl₂ (3 ml) wasadded mCPBA (65 mg, 0.32 mmol) and the reaction was stirred at roomtemperature for hours and was concentrated. The residue was purified byflash column chromatography on silica gel (100% EtOAc) to yield Compound42 (38 mg, 62%).

¹H NMR (300 MHz, CD₃OD) δ 8.24 (d, J=2.34 Hz, 1H), 8.07 (dd, J=2.34,10.26 Hz, 1H), 7.73-7.86 (m, 3H), 7.68 (s, 1H), 7.48-7.61 (m, 3H),7.29-7.45 (m, 3H).

EXAMPLE 87 Compound 432-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoicacid

To Compound 37 (76 mg, 0.15 mmol) in MeOH (5 ml) was added 5N NaOH (1ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 43 (67 mg, 90%).

¹H NMR (300 MHz, CD₃OD) δ 8.29 (d, J=2.05 Hz, 1H), 8.00 (d, J=2.05 Hz,1H), 7.91 (dd, J=1.76, 7.62 Hz, 1H), 7.75 (dd, J=1.03, 7.77 Hz, 1H),7.61 (s, 1H), 7.44-7.58 (m, 2H), 7.23-7.41 (m, 3H), 6.94 (dd, J=1.32,7.47 Hz, 2H), 4.94 (d, J=12.60 Hz, 1H), 4.81 (d, J=12.60 Hz, 1H).

EXAMPLE 88 Intermediate 47 5-methyl-3-nitro-2-(phenylthio)pyridine

To a solution of 2-chloro-5-methyl-3-nitropyridine (1.05 g, 5.44 mmol)in MeOH (10 ml) was added benzenethiol (0.56 ML, 5.44 mmol) and NaOH(1.5 ml, 5N) and the reaction was stirred at room temperature for 1.5hours, diluted with H₂O, and the resulting solution was extracted withEtOAc. The organic layer washed with brine, dried over Na₂SO₄ andconcentrated in vacuo, followed by MPLC purification to yieldIntermediate 47 (1.26 g, 88%) as a yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 8.29-8.36 (m, 2H), 7.50-7.59 (m, 2H),7.37-7.49 (m, 3H), 2.36 (t, J=0.73 Hz, 3H).

EXAMPLE 89 Intermediate 48 5-methyl-2-(phenylthio)pyridin-3-amine

To a solution of Intermediate 47 (1.26 g, 4.76 mmol) in MeOH (50 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (7.8 g, 119 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude Intermediate 49 (1.0 g, 91%) was used in the next reaction withoutfurther purification.

¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=1.47 Hz, 1H), 7.08-7.28 (m, 5H),6.86 (d, J=1.17 Hz, 1H), 4.18 (br. s., 2H), 2.27 (s, 3H).

EXAMPLE 90 Compound 44N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To Intermediate 49 (548 mg, 2.54 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (548 mg, 2.54 mmol) and the reaction wasstirred at 100° C. for 16 hours. Solvent was removed in vacuo and thecrude product was purified by flash column chromatography on silica gel(0-100% EtOAc in hexanes) to yield Compound 44 (691 mg, 69%).

¹H NMR (300 MHz, CD₃OD) δ 8.02 (dd, J=0.73, 2.20 Hz, 1H), 7.62-7.70 (m,2H), 7.38-7.56 (m, 2H), 7.25-7.36 (m, 2H), 7.02-7.20 (m, 3H), 6.86-6.98(m, 2H), 4.85 (br. s., 1H), 2.25 (s, 3H).

EXAMPLE 91 Compound 45N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 44 (106 mg, 0.27 mmol) in CH₂Cl₂ (3 ml) wasadded mCPBA (54 mg, 0.27 mmol) and the reaction was stirred at 0° C. for30 min and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 45 (59 mg,81%).

¹H NMR (300 MHz, CD₃OD) δ 8.19 (s, 1H), 7.82 (s, 1H), 7.70 (d, J=7.62Hz, 1H), 7.55-7.63 (m, 2H), 7.53 (s, 1H), 7.42-7.50 (m, 2H), 7.21-7.39(m, 4H), 2.30 (s, 3H).

EXAMPLE 92 Compound 46N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide

To a solution of Compound 44 (204 mg, 0.52 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (222 mg, 1.29 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 46 (141 mg, 64%).

¹H NMR (300 MHz, CD₃OD) δ 8.00 (d, J=9.67 Hz, 2H), 7.84 (d, J=7.62 Hz,2H), 7.64 (d, J=7.91 Hz, 1H), 7.21-7.55 (m, 7H), 2.28 (s, 3H).

EXAMPLE 93 Intermediate 49 methyl2-((5-chloro-3-nitropyridin-2-yl)thio)benzoate

To a solution of 2,5-dichloro-3-nitropyridine (1.0 g, 5.2 mmol) in MeOH(5 ml) was added methyl 2-mercaptobenzoate (0.71 ml, 5.2 mmol) and 4MNaOH (1.3 ml, 5.2 mmol) and the reaction was stirred at room temperaturefor 3 hours. The resulting suspension was diluted with H₂O and wasfiltered to give Intermediate 49 as yellow solid (1.74 g). The crudeproduct was used in the next reaction without further purification.

EXAMPLE 94 Intermediate 50 methyl2-((3-amino-5-chloropyridin-2-yl)thio)benzoate

To a solution of Intermediate 49 (1.7 g, 5.2 mmol) in HOAc (10 ml) wasadded iron powder (1.5 g, 26 mmol). The suspension was stirred at 70° C.for 1 hour and was diluted with MeOH, treated with Celite and wasfiltered. The filtrate was concentrated, then taken up in EtOAc, washedwith 4M NaOH, brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by flash column chromatography on silica gel(10-40% EtOAc in hexanes) to yield Intermediate 50 as light yellow solid(1.4 g, 91%).

1H NMR (METHANOL-d4) δ: 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.82-7.85 (m, 1H),7.30-7.37 (m, 1H), 7.19-7.27 (m, 2H), 6.74-6.79 (m, 1H), 3.92 (s, 3H).

EXAMPLE 95 Intermediate 51 methyl2-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2-yl)thio)benzoate

To Intermediate 50 (300 mg, 1.02 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (221 mg, 1.02 mmol) and a catalyticamount of DMAP. The reaction was stirred at 100° C. for a total of 42hours, during which additional benzofuran-2-sulfonyl chloride (553 mg,2.55 mmol) was added in three batches to drive the reaction towardcompletion. At the end the reaction was concentrated, acidified with 6MHCl, diluted with brine and extracted with EtOAc (×2). The combinedorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(15-20% EtOAc in hexanes) to yield Intermediate 51 (182 mg, 38%).

1H NMR (CHLOROFORM-d) δ: 8.36 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.06 (d,J=2.1 Hz, 1H), 7.79 (dd, J=7.9, 1.5 Hz, 1H), 7.49-7.53 (m, 1H),7.29-7.36 (m, 2H), 7.17-7.25 (m, 2H), 6.99 (td, J=7.6, 1.2 Hz, 1H),6.81-6.86 (m, 1H), 6.50 (dd, J=7.9, 0.9 Hz, 1H), 3.83 (s, 3H).

EXAMPLE 96 Compound 472-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid

To a solution of Intermediate 51 (60 mg, 0.13 mmol) in MeOH (5 ml) wasadded 4M NaOH (0.16 ml, 0.64 mmol) and the reaction was stirred at roomtemperature for 6 hours, when additional 4M NaOH (0.64 ml, 2.6 mmol) wasadded and the reaction was continued for 64 hours. The reaction was thenacidified with HCl, and concentrated. The crude product was trituratedwith MeOH to yield Compound 47 as an off-white solid (24 mg, 41%).

1H NMR (METHANOL-d4) δ: 8.28 (d, J=2.1 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H),7.81 (dd, J=7.8, 1.3 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.43 (d, J=3.5 Hz,2H), 7.37 (s, 1H), 7.27-7.34 (m, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (td,J=7.6, 1.5 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H).

EXAMPLE 97 Intermediate 52 methyl 3-((5-chloro3-nitropyridin-2-yl)thio)benzoate

To a solution of 2,5-dichloro-3-nitropyridine (1.15 g, 5.96 mmol) inMeOH (10 ml) was added methyl 3-mercaptobenzoate (1.0 g, 5.96 mmol) and4M NaOH (1.5 ml, 6.0 mmol) and the reaction was stirred at roomtemperature for 2 hours. The resulting suspension was diluted with H₂O,and it was filtered to give Intermediate 52 as yellow solid (1.94 g).The crude product was used in the next reaction without furtherpurification.

EXAMPLE 98 Intermediate 53 methyl3-((3-amino-5-chloropyridin-2-yl)thio)benzoate

To a solution of Intermediate 53 (324 mg, 1.0 mmol) in MeOH (15 ml) andTHF (15 ml) was added saturated aqueous NH₄Cl (20 ml) and zinc dust(1.63 g, 25 mmol). The suspension was stirred at room temperature for 1hour and was filtered, the filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The crude product was purified by flash column chromatographyon silica gel (20-30% EtOAc in hexanes) to yield Intermediate 53 (250mg, 85%).

¹H NMR (METHANOL-d4) δ: 7.82-7.86 (m, 1H), 7.79 (dt, J=7.6, 1.5 Hz, 1H),7.73 (d, J=2.1 Hz, 1H), 7.41 (dt, J=8.0, 1.4 Hz, 1H), 7.33 (t, J=7.6 Hz,1H), 7.16 (d, J=2.3 Hz, 1H), 3.83 (s, 3H).

EXAMPLE 99 Intermediate 54 methyl3-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2-yl)thio)benzoate

To Intermediate 53 (222 mg, 0.76 mmol) in pyridine (4 ml) was addedbenzofuran-2-sulfonyl chloride (164 mg, 0.76 mmol) and a catalyticamount of DMAP. The reaction was stirred at 100° C. for a total of 42hours, during which additional benzofuran-2-sulfonyl chloride (410 mg,1.9 mmol) was added in three batches to drive the reaction towardcompletion. At the end the reaction was concentrated, acidified with 6MHCl, diluted with brine and extracted with EtOAc (×2). The combinedorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (20%EtOAc in hexanes) to yield Intermediate 54 (275 mg, 77%).

¹H NMR (CHLOROFORM-d) δ: 8.23 (d, J=2.3 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H),7.84-7.90 (m, 2H), 7.68 (s, 1H), 7.65 (dt, J=7.8, 1.1 Hz, 1H), 7.44-7.48(m, 2H), 7.41 (d, J=0.6 Hz, 1H), 7.30-7.37 (m, 1H), 7.21-7.25 (m, 2H),3.87 (s, 3H).

EXAMPLE 100 Compound 483-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid

To a solution of Intermediate 54 (96 mg, 0.20 mmol) in MeOH (8 ml) wasadded 4M NaOH (0.25 ml, 1.0 mmol) and the reaction was stirred at roomtemperature for 6 hours, when an additional 4M NaOH (1.0 ml, 4.0 mmol)was added and the reaction was continued for 64 hours. The reaction wasthen acidified with HCl, concentrated. The crude product was trituratedwith H₂O to yield Compound 48 as an off-white solid (93 mg, 100%).

¹H NMR (METHANOL-d4) δ: 8.18 (d, J=2.1 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H),7.80 (d, J=2.3 Hz, 1H), 7.67-7.75 (m, 2H), 7.52-7.59 (m, 1H), 7.47 (t,J=7.8 Hz, 1H), 7.24-7.41 (m, 3H), 7.14 (d, J=7.9 Hz, 1H).

EXAMPLE 101 Compound 49 methyl2-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2-yl)sulfinyl)benzoate

To a solution of Intermediate 51 (58 mg, 0.12 mmol) in CH₂Cl₂ (2 ml) wasadded mCPBA (29 mg, ˜0.12 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 49 (56 mg, 93%).

¹H NMR (acetone) δ: 8.10-8.23 (m, 2H), 8.06 (d, J=6.2 Hz, 1H), 7.54-7.71(m, 4H), 7.46-7.54 (m, 1H), 7.32-7.44 (m, 2H), 7.23-7.32 (m, 1H), 3.61(s, 3H).

EXAMPLE 102 Compound 502-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoicacid

To a solution of Compound 49 (55 mg, 0.11 mmol) in MeOH (5 ml) was added4M NaOH (0.7 ml, 2.8 mmol) and the reaction was stirred at roomtemperature for 16 hours. The reaction was then acidified with HCl andwas concentrated. The crude product was triturated with H₂O to yieldCompound 50 as yellow solid (46 mg, 87%).

¹H NMR (CHLOROFORM-d) δ: 9.54 (br. s., 1H), 8.37 (d, J=8.2 Hz, 1H), 8.19(d, J=2.1 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.04 (dd, J=7.5, 1.0 Hz, 1H),7.77-7.85 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.52-7.61 (m, 2H), 7.49 (s,1H), 7.44 (td, J=7.8, 1.3 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H).

EXAMPLE 103 Compound 51 methyl2-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2-yl)sulfonyl)benzoate

To a solution of Intermediate 51 (58 mg, 0.12 mmol) in CH₂Cl₂ (2 ml) wasadded mCPBA (59 mg, ˜0.25 mmol) and the reaction was stirred at roomtemperature for 2 hours and additional mCPBA (30 mg, ˜0.12 mmol) wasadded. The reaction was continued for 4 hours and was diluted withsaturated aqueous NaHCO₃, extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (50%EtOAc in hexanes) to yield Compound 51 (45 mg, 73%).

¹H NMR (acetone) δ: 8.13-8.21 (m, 1H), 8.08 (br. s., 1H), 7.51-7.74 (m,5H), 7.11-7.47 (m, 5H), 3.50 (br. s., 3H).

EXAMPLE 104 Compound 522-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoicacid

To a solution of Compound 51 (45 mg, 0.089 mmol) in MeOH (5 ml) wasadded 4M NaOH (0.56 ml, 2.2 mmol) and the reaction was stirred at roomtemperature for 2 days. The reaction was then acidified with HCl and wasconcentrated. The crude product was triturated with H₂O and was furtherpurified by PTLC (developed with EtOAc) to yield Compound 52 as whitesolid (20 mg, 45%).

¹H NMR (CHLOROFORM-d) δ: 9.77 (s, 1H), 8.42-8.45 (m, 1H), 8.30 (d, J=2.1Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 8.04-8.06 (m, 1H), 7.76-7.79 (m, 2H),7.68-7.70 (m, 1H), 7.58-7.60 (m, 1H), 7.55 (d, J=0.9 Hz, 1H), 7.49 (ddd,J=8.5, 7.2, 1.3 Hz, 1H), 7.35 (ddd, J=7.9, 7.0, 0.9 Hz, 1H).

EXAMPLE 106 Intermediate 55 methyl2-(((5-methyl-3-nitropyridin-2-yl)thio)methyl)benzoate

To the crude Intermediate 54 in DMF (10 ml) was added methyl2-(bromomethyl)benzoate (1.4 g, 6.20 mmol) and K₂CO₃ (2.5 g, 18.11 mmol)and the reaction was stirred at room temperature for 16 hours. Thereaction mixture was poured into water (50 ml) and extracted with ethylacetate (2×50 ml). The organic layer was washed with brine and thendried over Na₂SO₄ anhydride, concentrated in vacuo and purified by flashcolumn chromatography on silica gel (0˜30% ethyl acetate in hexane) togive Intermediate 55 (555 mg, 31%).

¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J=1.47 Hz, 1H), 8.28 (d, J=1.47 Hz,1H), 7.92 (dd, J=1.17, 7.91 Hz, 1H), 7.59 (d, J=7.62 Hz, 1H), 7.42 (td,J=1.32, 7.55 Hz, 1H), 7.21-7.35 (m, 1H), 4.88 (s, 2H), 3.93 (s, 3H),2.39 (s, 3H).

EXAMPLE 107 Intermediate 56 methyl2-(((3-amino-5-methylpyridin-2-yl)thio)methyl)benzoate

To a solution Intermediate 55 (555 mg, 1.94 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (3.2 g, 63.71 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, and the filtrate was extracted with EtOAc (×2). The organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude Intermediate 56 (406 mg, 81%) was used in the nextreaction without further purification.

¹H NMR (300 MHz, CD₃OD) δ 7.83 (dd, J=1.47, 7.62 Hz, 1H), 7.65 (d,J=1.17 Hz, 1H), 7.13-7.38 (m, 3H), 6.83 (d, J=1.17 Hz, 1H), 4.58 (s,2H), 3.86 (s, 3H), 2.18 (s, 3H).

EXAMPLE 108 Intermediate 57 methyl2-(((3-(benzofuran-2-sulfonamido)-5-methylpyridin-2-yl)thio)methyl)benzoate

To Intermediate 56 (406 mg, 1.41 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (305 mg, 1.41 mmol), and the reaction wasstirred at 100° C. for 16 hours and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silica gel (0-30%EtOAc in hexanes) to yield Intermediate 57 (270 mg, 41%).

¹H NMR (600 MHz, CDCl₃) δ 8.15 (dd, J=0.59, 2.05 Hz, 0H), 7.88 (dd,J=1.61, 7.48 Hz, 0H), 7.65-7.70 (m, 1H), 7.63-7.65 (m, 0H), 7.59 (ddd,J=0.88, 1.03, 8.07 Hz, 0H), 7.43 (dd, J=1.17, 6.75 Hz, 0H), 7.21-7.31(m, 4H), 7.17 (dd, J=1.61, 7.48 Hz, 1H), 4.63 (s, 2H), 3.91 (s, 3H),2.30 (s, 3H).

EXAMPLE 109 Compound 532-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfanyl)methyl]benzoicacid

To Intermediate 57 (136 mg, 0.29 mmol) in MeOH (30 ml) was added 5N NaOH(2 ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 53 (108 mg, 82%).

¹H NMR (600 MHz, CDCl₃) δ 8.05 (s, 1H), 7.80 (dd, J=1.47, 7.63 Hz, 1H),7.69 (s, 1H), 7.62 (d, J=7.92 Hz, 1H), 7.52-7.56 (m, 1H), 7.49 (td,J=1.32, 7.85 Hz, 1H), 7.33-7.37 (m, J=7.48, 7.48 Hz, 1H), 7.28 (d,J=0.88 Hz, 1H), 7.23 (td, J=1.17, 7.48 Hz, 1H), 7.18 (td, J=1.47, 7.48Hz, 1H), 7.10 (d, J=7.63 Hz, 1H), 7.03 (br. s., 1H), 4.47 (s, 2H), 2.29(s, 3H).

EXAMPLE 110 Compound 54 methyl2-(((3-(benzofuran-2-sulfonamido)-5-methylpyridin-2-yl)sulfinyl)methyl)benzoate

To a solution of Intermediate 57 (134 mg, 0.29 mmol) in CH₂Cl₂ (5 ml)was added mCPBA (57 mg, 0.29 mmol) and the reaction was stirred at 0° C.for 30 mins and was concentrated. The residue was purified by flashcolumn chromatography on silica gel (100% EtOAc) to yield Compound 54(82 mg, 59%).

¹H NMR (600 MHz, CDCl₃) δ 10.84 (br. s., 1H), 8.07 (d, J=1.17 Hz, 1H),7.98 (dd, J=1.32, 7.78 Hz, 1H), 7.87 (s, 1H), 7.65 (d, J=7.92 Hz, 1H),7.44-7.48 (m, 2H), 7.38-7.43 (m, 2H), 7.34-7.38 (m, 1H), 7.27-7.32 (m,1H), 7.01-7.09 (m, 1H), 4.98 (d, J=12.32 Hz, 1H), 4.63 (d, J=12.32 Hz,1H), 3.87 (s, 3H), 2.36 (s, 3H).

EXAMPLE 111 Compound 552-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoicacid

To Compound 54 (505 mg, 1.04 mmol) in MeOH (30 ml) was added 5N NaOH (2ml) and the reaction was stirred at room temperature for 16 hours. Themixture was acidified with 10% HCl, and extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 55 (454 mg, 93%).

¹H NMR (600 MHz, CDCl₃) δ 8.05-8.16 (m, 2H), 7.90 (s, 1H), 7.68 (dd,J=0.73, 7.78 Hz, 1H), 7.37-7.52 (m, 5H), 7.33 (td, J=1.03, 7.56 Hz, 1H),7.04 (d, J=7.34 Hz, 1H), 4.97 (d, J=11.74 Hz, 1H), 4.63 (d, J=12.03 Hz,1H), 2.41 (s, 3H).

EXAMPLE 112 Intermediate 58 methyl2-(((3-nitropyridin-2-yl)thio)methyl)benzoate

To 3-nitropyridine-2-thiol (1 g, 6.40 mmol) in DMF (10 ml) was addedmethyl 2-(bromomethyl)benzoate (1.5 g, 6.40 mmol) and K₂CO₃ (2.6 g,19.21 mmol) and the reaction was stirred at room temperature for 16hours. The reaction mixture was poured into water (50 ml) and extractedwith ethyl acetate (2×50 ml). The organic layer was washed with brineand then dried over Na₂SO₄, concentrated in vacuo and purified by flashcolumn chromatography on silica gel (0˜30% ethyl acetate in hexane) togive Intermediate 58 (1.12 g, 57%).

¹H NMR (600 MHz, CDCl₃) δ 8.70 (dd, J=1.61, 4.55 Hz, 1H), 8.47 (dd,J=1.47, 8.22 Hz, 1H), 7.95 (dd, J=1.17, 7.63 Hz, 1H), 7.62 (d, J=7.92Hz, 1H), 7.44 (td, J=1.32, 7.56 Hz, 1H), 7.29-7.36 (m, 1H), 7.19 (dd,J=4.55, 8.36 Hz, 1H), 4.92 (s, 2H), 3.94 (s, 3H).

EXAMPLE 113 Intermediate 59 methyl2-(((3-aminopyridin-2-yl)thio)methyl)benzoate

To a solution of Intermediate 58 (555 mg, 3.68 mmol) in MeOH (20 ml) wasadded saturated aqueous NH₄Cl (2 ml) and zinc dust (4.8 g, 73.68 mmol).The suspension was stirred at room temperature for 1 hour and wasfiltered, the filtrate was extracted with EtOAc (×2). The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated in vacuo.Intermediate 59 (988 mg, 98%) was used in the next reaction withoutfurther purification.

¹H NMR (600 MHz, CDCl₃) δ 8.15 (dd, J=0.59, 2.05 Hz, 1H), 7.88 (dd,J=1.61, 7.48 Hz, 1H), 7.65-7.70 (m, 1H), 7.63-7.65 (m, 1H), 7.59 (ddd,J=0.88, 1.03, 8.07 Hz, 1H), 7.43 (dd, J=1.17, 6.75 Hz, 1H), 7.21-7.31(m, 4H), 7.17 (dd, J=1.61, 7.48 Hz, 1H), 4.63 (s, 2H), 3.91 (s, 3H),2.30 (s, 3H).

EXAMPLE 114 Compound 56 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoate

To Intermediate 59 (968 mg, 3.53 mmol) in pyridine (5 ml) was addedbenzofuran-2-sulfonyl chloride (763 mg, 1.41 mmol) and the reaction wasstirred at 100° C. for 16 hours, then additional ofbenzofuran-2-sulfonyl chloride (763 mg, 1.41 mmol) and DMAP (cat.) wasadded and the reaction was further stirred at 100° C. for 16 hours andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound56 (745 mg, 46%).

¹H NMR (600 MHz, CDCl₃) δ 8.55 (br. s., 1H), 8.24 (dd, J=1.47, 4.70 Hz,1H), 7.81 (d, J=7.92 Hz, 1H), 7.71 (dd, J=1.61, 8.07 Hz, 1H), 7.50-7.53(m, 1H), 7.31-7.40 (m, 2H), 7.13-7.25 (m, 5H), 6.99 (dd, J=4.70, 8.22Hz, 1H), 4.62 (s, 2H), 3.83 (s, 3H).

EXAMPLE 115 Compound 572-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoicacid

To Compound 56 (170 mg, 0.37 mmol) in MeOH (30 ml) was added 5N NaOH (2ml) and stirred at room temperature for 3 hours. The mixture wasacidified with 10% HCl, extracted with EtOAc (×2). The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was recrystallized from minimal MeOH and CH₂Cl₂to yield Compound 57 (165 mg, 100%).

¹H NMR (600 MHz, CDCl₃) δ 8.33 (br. s., 1H), 7.89 (none, 1H), 7.86-7.91(m, 1H), 7.78 (d, J=7.92 Hz, 1H), 7.60 (d, J=7.92 Hz, 0H), 7.42-7.48 (m,2H), 7.29-7.35 (m, 2H), 7.22-7.26 (m, 3H), 7.16-7.20 (m, 1H), 7.13 (br.s., 1H), 4.64 (s, 2H).

EXAMPLE 116 Compound 58 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-Yl}sulfinyl)methyl]benzoate

To a solution of Compound 56 (180 mg, 0.40 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (80 mg, 0.40 mmol) and the reaction was stirred at 0° C. for30 mins and was concentrated. The residue was purified by flash columnchromatography on silica gel (100% EtOAc) to yield Compound 58 (180 mg,96%).

¹H NMR (600 MHz, CDCl₃) δ 8.22 (ddd, J=1.32, 1.47, 4.55 Hz, 1H),8.03-8.08 (m, 1H), 7.96 (dd, J=1.47, 7.63 Hz, 1H), 7.63 (dd, J=0.59,7.92 Hz, 1H), 7.22-7.49 (m, 7H), 7.01 (d, J=7.63 Hz, 1H), 5.02 (d,J=12.32 Hz, 1H), 4.66 (d, J=12.32 Hz, 1H), 3.86 (s, 3H).

EXAMPLE 117 Compound 592-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoicacid

To Compound 58 (189 mg, 0.40 mmol) in MeOH (30 ml) was added 5N NaOH (2ml) and stirred at room temperature for 3 hours. The mixture wasacidified with 10% HCl, extracted with EtOAc (×2). The combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was recrystallized from minimal MeOH and CH₂Cl₂to yield Compound 59 (140 mg, 76%).

¹H NMR (600 MHz, CD₃OD) δ 8.30 (d, J=3.52 Hz, 1H), 7.95-8.02 (m, 1H),7.84 (s, 1H), 7.72 (d, J=7.92 Hz, 1H), 7.51-7.57 (m, 2H), 7.41-7.49 (m,2H), 7.29-7.37 (m, 3H), 6.83-6.92 (m, 1H), 4.96 (d, J=12.32 Hz, 1H),4.80 (d, J=12.32 Hz, 1H).

EXAMPLE 118 Compound 60 methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoate

To a solution of Compound 56 (180 mg, 0.40 mmol) in CH₂Cl₂ (5 ml) wasadded mCPBA (200 mg, 0.99 mmol) and the reaction was stirred at roomtemperature for 2 hours and was concentrated. The residue was purifiedby flash column chromatography on silica gel (100% EtOAc) to yieldCompound 60 (186 mg, 97%).

¹H NMR (600 MHz, CDCl₃) δ 9.62 (br. s., 1H), 8.39 (d, J=4.40 Hz, 1H),8.19 (d, J=8.80 Hz, 1H), 7.89 (d, J=7.92 Hz, 1H), 7.63 (d, J=7.92 Hz,1H), 7.41-7.51 (m, 4H), 7.33-7.38 (m, 1H), 7.27-7.32 (m, 2H), 7.18 (d,J=7.34 Hz, 1H), 5.31 (s, 2H), 3.86 (s, 3H).

EXAMPLE 119 Compound 612-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoicacid

To Compound 60 (119 mg, 0.24 mmol) in MeOH (30 ml) was added 5N NaOH (2ml) and the reaction was stirred at room temperature for 3 hours. Themixture was acidified with 10% HCl, extracted with EtOAc (×2). Thecombined organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was recrystallized from minimalMeOH and CH₂Cl₂ to yield Compound 61 (98 mg, 85%).

¹H NMR (600 MHz, CD₃OD) δ 8.41 (dd, J=1.17, 4.40 Hz, 1H), 8.20 (dd,J=1.32, 8.66 Hz, 1H), 7.86 (dd, J=1.32, 7.78 Hz, 1H), 7.73 (d, J=7.92Hz, 1H), 7.63 (dd, J=4.40, 8.51 Hz, 1H), 7.58 (d, J=0.88 Hz, 1H),7.53-7.56 (m, 1H), 7.48-7.53 (m, 1H), 7.36 (td, J=1.03, 7.56 Hz, 1H),7.29-7.33 (m, 1H), 7.23 (td, J=1.47, 7.63 Hz, 1H), 7.13 (dd, J=0.88,7.63 Hz, 1H), 5.39 (s, 2H).

BIOLOGICAL DATA

HEK-Gqi5 cells stably expressing CCR2 were cultured in (DMEM highglucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin.Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) wasused as the positive control agonist for screening compound-inducedcalcium activity assayed on the FLIPR^(Tetra). The drug plates wereprepared in 384-well microplates using the EP3 and the MultiPROBErobotic liquid handling systems. Compounds were synthesized and testedfor CCR2 activity.

Table 1 shows activity: CCR2 receptor (IC₅₀) nM

TABLE 1 IUPAC Name IC50 (nM) % ANTAGONISMN-[2-(benzylsulfanyl)-5-chloropyridin- 252 833-yl]-1-benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-5-chloropyridin-31 94 3-yl]-1-benzofuran-2-sulfonamideN-[2-(benzylsulfonyl)-5-chloropyridin- 19 903-yl]-1-benzofuran-2-sulfonamide N-{5-chloro-2-[(pyridin-3- 32 95ylmethyl)sulfanyl]pyridin-3-yl}-1- benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-3- 201 99 ylmethyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide N-{5-chloro-2-[(pyridin-3- 2142 84ylmethyl)sulfonyl]pyridin-3-yl}-1- benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-oxidopyridin-3- 130 100yl)methyl]sulfonyl}pyridin-3-yl)-1- benzofuran-2-sulfonamideN-[2-(benzylsulfanyl)pyridin-3-yl]-1- 3012 80 benzofuran-2-sulfonamideN-[2-(benzylsulfinyl)pyridin-3-yl]-1- 27 100 benzofuran-2-sulfonamideN-[2-(benzylsulfonyl)pyridin-3-yl]-1- 16 95 benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)sulfanyl]pyridin- 102 993-yl}-1-benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)sulfinyl]pyridin-255 100 3-yl}-1-benzofuran-2-sulfonamide tert-butyl{3-[({3-[(1-benzofuran-2- 497 102 ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]phenyl}carbamateN-{2-[(3-aminobenzyl)sulfonyl]pyridin- 71 1023-yl}-1-benzofuran-2-sulfonamide N-[2-(benzylsulfanyl)-5-fluoropyridin-125 94 3-yl]-1-benzofuran-2-sulfonamideN-[2-(benzylsulfinyl)-5-fluoropyridin-3- 18 95yl]-1-benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)-5-fluoropyridin- 43101 3-yl]-1-benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)sulfanyl]-5-95 98 chloropyridin-3-yl}-1-benzofuran-2- sulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5- 101 97chloropyridin-3-yl}-1-benzofuran-2- sulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5- 142 100chloropyridin-3-yl}-1-benzofuran-2- sulfonamideN-[2-(benzylsulfanyl)-5-methylpyridin- 194 803-yl]-1-benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-5-methylpyridin-25 103 3-yl]-1-benzofuran-2-sulfonamideN-[2-(benzylsulfonyl)-5-methylpyridin- 12 963-yl]-1-benzofuran-2-sulfonamide N-{5-chloro-2-[(2-methylpyridin-3- 3490 yl)oxy]pyridin-3-yl}-1-benzofuran-2- sulfonamide2-({3-[(1-benzofuran-2- 157 97 ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoic acid methyl 2-({3-[(1-benzofuran-2- 215 93ylsulfonyl)amino]-5-chloropyridin-2- yl}oxy)benzoateN-{5-chloro-2-[(4-oxopiperidin-1- 24 105 yl)carbonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide N-[5-chloro-2-(phenylcarbonyl)pyridin- 36 1003-yl]-1-benzofuran-2-sulfonamide N-[5-chloro-2-(phenylsulfonyl)pyridin-17 105 3-yl]-1-benzofuran-2-sulfonamideN-[5-chloro-2-(phenylsulfinyl)pyridin- 7 993-yl]-1-benzofuran-2-sulfonamide N-{5-chloro-2-[(2-methylpyridin-3- 251102 yl)methoxy]pyridin-3-yl}-1- benzofuran-2-sulfonamide methyl2-[({3-[(1-benzofuran-2- 4252 91 ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoate 2-[({3-[(1-benzofuran-2- 340 97ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfanyl)methyl]benzoic acidmethyl 2-[({3-[(1-benzofuran-2- 191 95ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfinyl)methyl]benzoate methyl2-[({3-[(1-benzofuran-2- 180 97 ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoate 2-[({3-[(1-benzofuran-2- 2691 32ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfonyl)methyl]benzoic acidN-[5-fluoro-2-(phenylsulfanyl)pyridin- 469 653-yl]-1-benzofuran-2-sulfonamideN-[5-fluoro-2-(phenylsulfinyl)pyridin-3- 68 97yl]-1-benzofuran-2-sulfonamide 2-[({3-[(1-benzofuran-2- nd 90ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfinyl)methyl]benzoic acidN-[5-methyl-2-(phenylsulfinyl)pyridin- 455 1053-yl]-1-benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfonyl)pyridin-1436 57 3-yl]-1-benzofuran-2-sulfonamide 2-({3-[(1-benzofuran-2- 1230102 ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfanyl)benzoic acid3-({3-[(1-benzofuran-2- 786 96 ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid 2-({3-[(1-benzofuran-2- 1951 5ylsulfonyl)amino]-5-chloropyridin-2- yl}sulfinyl)benzoic acid methyl2-[({3-[(1-benzofuran-2- 1754 92 ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoate 2-[({3-[(1-benzofuran-2- 493 98ylsulfonyl)amino]pyridin-2- yl}sulfanyl)methyl]benzoic acid methyl2-[({3-[(1-benzofuran-2- 198 102 ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate 2-[({3-[(1-benzofuran-2- nd 58ylsulfonyl)amino]pyridin-2- yl}sulfinyl)methyl]benzoic acid methyl2-[({3-[(1-benzofuran-2- 86 101 ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoate 2-[({3-[(1-benzofuran-2- nd 57ylsulfonyl)amino]pyridin-2- yl}sulfonyl)methyl]benzoic acid

What is claimed is:
 1. A method of treating a disorder associated withchemokine receptor modulation, which comprises administering to a mammalin need thereof, a pharmaceutical composition comprising atherapeutically effective amount of at least one compound of Formula I

wherein: R¹ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R² is hydrogen, halogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R³ is hydrogen,halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, orCOR¹⁵; R⁴ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁵ is hydrogen, halogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁶ is hydrogen,halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, orCOR¹⁵; R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁸ is hydrogen, halogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁹ is O, C(O), S,S(O), S(O)₂, —C(═NOR¹⁶)—; a is 0 or 1; R¹¹ is hydrogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, CF₃, OR¹², NR¹³R¹⁴, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₂₋₆ alkyne, substituted or unsubstituted C₂₋₆ alkene orCOR¹⁵; R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; R¹³is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or can from anoptionally substituted heterocycle with R¹⁴; R¹⁴ is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted C₆₋₁₀ aryl or can from anoptionally substituted heterocycle with R¹³; R¹⁵ is hydrogen, hydroxyl,substituted or unsubstituted heterocycle, substituted or unsubstitutedC₆₋₁₀ aryl or substituted or unsubstituted C₁₋₆ alkyl; R¹⁶ is hydrogenor substituted or unsubstituted C₁₋₆ alkyl; and R¹⁸ is hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl; wherein the disorder associatedwith chemokine receptor modulation is: an ocular inflammatory diseaseselected from: uveitis, retinal degenerative conditions, angiogenesis,dry eve, Keratitis, allergic eve disease, conditions affecting theposterior part of the eye, retinal degeneration, non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy, acutemacular neuroretinopathy, central serous chorioretinopathy, cystoidmacular edema, and diabetic macular edema, retinitis, acute multifocalplacoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, multifocal choroiditis, multiple evanescent whitedot syndrome, ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and Vogt-Koyanagi-and Harada syndrome;or a skin inflammatory disease selected from: rosacea , sunburn, chronicsun damage, discreet erythemas, psoriasis, atopic dermatitis,menopause-associated hot flashes, hot flashes resulting fromorchiectomvatopic dermatitis, photoaging, seborrheic dermatitis, acne,allergic dermatitis, irritant dermatitis, telangiectasia of the face,rhinophyma , red bulbous nose, acne-like skin eruptions, burning orstinging sensation of the face, cutaneous hyperactivity with dilation ofblood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome,erythema multiforme minor, erythema multiforme, actinic keratoses,arsenic keratoses, inflammatory acne, non inflammatory acne, eczema andwound healing.
 2. The method according to claim 1 wherein: R¹ ishydrogen, halogen or substituted or unsubstituted C₁₋₆ alkyl; R² ishydrogen, halogen or substituted or unsubstituted C₁₋₆ alkyl; R³ ishydrogen, halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁴ ishydrogen, halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁵ ishydrogen, halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁶ ishydrogen, halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹²,NR¹³R¹⁴, or COR¹⁵; R⁷ is hydrogen, halogen, CN, substituted orunsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁸ is hydrogen,halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, orCOR¹⁵; R⁹ is S, S(O), S(O)₂; a is 0 or 1; R¹¹ is hydrogen, CN,substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹², NR¹³R¹⁴, substitutedor unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₂₋₆ alkyne, substituted or unsubstituted C₂₋₆ alkene orCOR¹⁵; R¹² is hydrogen or substituted or unsubstituted C₁₋₆ alkyl; R¹³is hydrogen or substituted or unsubstituted C₁₋₆ alkyl or can from anoptionally substituted heterocycle with R¹⁴; R¹⁴ is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted C₆₋₁₀ aryl or can from anoptionally substituted heterocycle with R¹³; R¹⁵ is hydrogen, hydroxyl,substituted or unsubstituted heterocycle, substituted or unsubstitutedC₆₋₁₀ aryl or substituted or unsubstituted C₁₋₆ alkyl; and R¹⁸ ishydrogen or substituted or unsubstituted C₁₋₆ alkyl.
 3. The methodaccording to claim 1 wherein the compound of Formula I is selected from:N-[2-(benzylthio)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1-benzofuran-2-sulfonamide;N-[2-(benzylthio)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;tert-butyl{3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]phenyl}carbamate;N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}1-benzofuran-2-sulfonamide;N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}1-benzofuran-2-sulfonamide;N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoate;methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoicacid;N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoicacid;N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid;3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoicacid;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoicacid;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfanyl)methyl]benzoicacid;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoate;and2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoicacid.
 4. The method of claim 1, wherein: R¹ is hydrogen, halogen orsubstituted or unsubstituted C₁₋₆ alkyl; R² is hydrogen, halogen orsubstituted or unsubstituted C₁₋₆ alkyl; R³ is hydrogen, halogen orsubstituted or unsubstituted C₁₋₆ alkyl; R⁴ is hydrogen, halogen orsubstituted or unsubstituted C₁₋₆ alkyl; R⁵ is hydrogen, halogen orsubstituted or unsubstituted C₁₋₆ alkyl; R⁶ is hydrogen, halogen, CN,substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁷ ishydrogen, halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹²,NR¹³R¹⁴, or COR¹⁵; R⁸ is hydrogen, halogen, CN, substituted orunsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁹ is O; a is 0 or 1;R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃, OR¹²,NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₃₋₈ cycloalkyl,substituted or unsubstituted C₂₋₆ alkyne, substituted or unsubstitutedC₂₋₆ alkene or COR¹⁵; R¹² is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl; R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkylor can from an optionally substituted heterocycle with R¹⁴; R¹⁴ ishydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted C₆₋₁₀ aryl orcan from an optionally substituted heterocycle with R¹³; R¹⁵ ishydrogen, hydroxyl, substituted or unsubstituted heterocycle,substituted or unsubstituted C₆₋₁₀ aryl or substituted or unsubstitutedC₁₋₆ alkyl; and R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆alkyl.
 5. The method according to claim 1 wherein: R¹ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R² is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R³ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁴ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁵ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁶ is hydrogen,halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, orCOR¹⁵; R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁸ is hydrogen, halogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁹ is C(O); a is 0or 1; R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆ alkyl, CF₃,OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₃₋₈ cycloalkyl,substituted or unsubstituted C₂₋₆ alkyne, substituted or unsubstitutedC₂₋₆ alkene or COR¹⁵; R¹² is hydrogen or substituted or unsubstitutedC₁₋₆ alkyl; R¹³ is hydrogen or substituted or unsubstituted C₁₋₆ alkylor can from an optionally substituted heterocycle with R¹⁴; R¹⁴ ishydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted C₆₋₁₀ aryl orcan from an optionally substituted heterocycle with R¹³; R¹⁵ ishydrogen, hydroxyl, substituted or unsubstituted heterocycle,substituted or unsubstituted C₆₋₁₀ aryl or substituted or unsubstitutedC₁₋₆ alkyl; and R¹⁸ is hydrogen or substituted or unsubstituted C₁₋₆alkyl.
 6. The method according to claim 1 wherein: R¹ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R² is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R³ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁴ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁵ is hydrogen,halogen or substituted or unsubstituted C₁₋₆ alkyl; R⁶ is hydrogen,halogen, CN, substituted or unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, orCOR¹⁵; R⁷ is hydrogen, halogen, CN, substituted or unsubstituted C₁₋₆alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁸ is hydrogen, halogen, CN, substitutedor unsubstituted C₁₋₆ alkyl, OR¹², NR¹³R¹⁴, or COR¹⁵; R⁹ is —C(═NOR¹⁶)—;a is 0 or 1; R¹¹ is hydrogen, CN, substituted or unsubstituted C₁₋₆alkyl, CF₃, OR¹², NR¹³R¹⁴, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted heterocycle, substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₂₋₆ alkyne, substitutedor unsubstituted C₂₋₆ alkene or COR¹⁵; R¹² is hydrogen or substituted orunsubstituted C₁₋₆ alkyl; R¹³ is hydrogen or substituted orunsubstituted C₁₋₆ alkyl or can from an optionally substitutedheterocycle with R¹⁴; R¹⁴ is hydrogen, substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted heterocycle or substituted orunsubstituted C₆₋₁₀ aryl or can from an optionally substitutedheterocycle with R¹³; R¹⁵ is hydrogen, hydroxyl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₆₋₁₀ aryl orsubstituted or unsubstituted C₁₋₆ alkyl; R¹⁶ is hydrogen or substitutedor unsubstituted C₁₋₆ alkyl; and R¹⁸ is hydrogen or substituted orunsubstituted C₁₋₆ alkyl.
 7. The method according to claim 1 wherein thecompound of Formula I is selected from:N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-(5-chloro-2{-[(1-oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;tert-butyl{3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]phenyl}carbamate;N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoicacid; methyl2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate;N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-{5-chloro-2-[(2-methylpyridin-3-yl)methoxy]pyridin-3-yl}-1-benzofuran-2-sulfonamide;N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoate;methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoicacid;N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoicacid;N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1-benzofuran-2-sulfonamide;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid;3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoicacid;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoicacid;2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoicacid;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfanyl)methyl]benzoicacid;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate;2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoicacid; methyl2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoate;and2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoicacid.
 8. The method of claim 1 wherein the mammal is a human.